Autoimmunity, cancer and COVID-19 abnormally activate wound healing pathways: critical role of inflammation

Abramenko N, Vellieux F, Tesařová P et al (2021) Estrogen receptor modulators in viral infections such as SARS−CoV−2: therapeutic consequences. Int J Mol Sci 22(12):6551. https://doi.org/10.3390/ijms22126551 Adamik B, Zimecki M, Właszczyk A, Kübler A (1997) Immunological status of septic and trauma patients. I. High tumor necrosis factor α serum levels in septic and trauma patients are not responsible for increased mortality; a prognostic value of serum interleukin 6. Arch Immunol Ther Exp 45(2–3):169–175 (PMID: 9597083) Albrecht LJ, Tauber SC, Merres J et al (2016) Lack of proinflammatory cytokine interleukin-6 or tumor necrosis factor receptor-1 results in a failure of the innate immune response after bacterial meningitis. Mediators Inflamm. https://doi.org/10.1155/2016/7678542 Amer H, Kartikasari AER, Plebanski M (2021) Elevated interleukin-6 levels in the circulation and peritoneal fluid of patients with ovarian cancer as a potential diagnostic biomarker: a systematic review and meta-analysis. J Pers Med. https://doi.org/10.3390/JPM11121335 Aul DR, Gates DJ, Draper DA et al (2021) Complications after discharge with COVID-19 infection and risk factors associated with development of post-COVID pulmonary fibrosis. Respir Med. https://doi.org/10.1016/j.rmed.2021.106602 Avazi DO, Awasum AC, Hassan AZ et al (2019) Evaluation of levels of interleukin-6, interleukin-8 and some haematologic parameters of dogs with cutaneous wounds. Cytokine. https://doi.org/10.1016/j.cyto.2018.06.024 Barbé-Tuana F, Funchal G, Schmitz CRR et al (2020) The interplay between immunosenescence and age-related diseases. Semin Immunopathol 42(5):545–557. https://doi.org/10.1007/s00281-020-00806-z Barleon B, Sozzani S, Zhou D et al (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343. https://doi.org/10.1182/BLOOD.V87.8.3336.BLOODJOURNAL8783336 Bauer ME, de la Fuente M (2016) The role of oxidative and inflammatory stress and persistent viral infections in immunosenescence. Mech Ageing Dev 158:27–37. https://doi.org/10.1016/j.mad.2016.01.001 Bleve A, Motta F, Durante B et al (2022) Immunosenescence, inflammaging, and frailty: role of myeloid cells in age-related diseases. Clin Rev Allergy Immunol 1:1. https://doi.org/10.1007/S12016-021-08909-7 Bonner JC, Badgett A, Osornio-Vargas AR et al (1990) PDGF-stimulated fibroblast proliferation is enhanced synergistically by receptor-recognized alpha 2-macroglobulin. J Cell Physiol 145:1–8. https://doi.org/10.1002/JCP.1041450102 Borsky J, Veleminska J, Jurovčík M et al (2012) Successful early neonatal repair of cleft lip within first 8 days of life. Int J Pediatr Otorhinolaryngol 76:1616–1626. https://doi.org/10.1016/J.IJPORL.2012.07.031 Brábek J, Jakubek M, Vellieux F et al (2020) Interleukin-6: molecule in the intersection of cancer, ageing and COVID-19. Int J Mol Sci 21:1–25. https://doi.org/10.3390/IJMS21217937 Bridges JP, Vladar EK, Huang H, Mason RJ (2022) Respiratory epithelial cell responses to SARS-CoV-2 in COVID-19. Thorax 77:203–209. https://doi.org/10.1136/THORAXJNL-2021-217561 Bustamante MF, Garcia-Carbonell R, Whisenant KD, Guma M (2017) Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res Ther. https://doi.org/10.1186/S13075-017-1303-3 Cámara-Lemarroy CR, Guzmán-De La Garza FJ, Fernández-Garza NE (2010) Molecular inflammatory mediators in peripheral nerve degeneration and regeneration. NeuroImmunoModulation 17:314–324. https://doi.org/10.1159/000292020 Chimenti MS, Fonti GL, Conigliaro P et al (2021) The burden of depressive disorders in musculoskeletal diseases: is there an association between mood and inflammation? Ann Gen Psychiatry. https://doi.org/10.1186/S12991-020-00322-2 Chitturi RT, Balasubramaniam AM, Parameswar RA et al (2015) The role of myofibroblasts in wound healing, contraction and its clinical implications in cleft palate repair. J Int Oral Health 7:75 (PMID: 25878485; PMCID: PMC4385733) Clark RA, McCOY GA, Folkvord JM, McPHERSON JM (1997) TGF-β1 stimulates cultured human fibroblasts to proliferate and produce tissue-like fibroplasia: a fibronectin matrix-dependent event. J Cell Physiol 170:69–80. https://doi.org/10.1002/(SICI)1097-4652(199701)170:1 Cobianchi S, de Cruz J, Navarro X (2014) Assessment of sensory thresholds and nociceptive fiber growth after sciatic nerve injury reveals the differential contribution of collateral reinnervation and nerve regeneration to neuropathic pain. Exp Neurol 255:1–11. https://doi.org/10.1016/J.EXPNEUROL.2014.02.008 Čoma M, Fröhlichová L, Urban L et al (2021) Molecular changes underlying hypertrophic scarring following burns involve specific deregulations at all wound healing stages (inflammation, proliferation and maturation). Int J Mol Sci 22:1–20. https://doi.org/10.3390/IJMS22020897 d’Alessandro M, Perillo F, Metella Refini R et al (2020) Efficacy of baricitinib in treating rheumatoid arthritis: modulatory effects on fibrotic and inflammatory biomarkers in a real-life setting. Int Immunopharmacol. https://doi.org/10.1016/J.INTIMP.2020.106748 de Oliveira S, Rosowski EE, Huttenlocher A (2016) Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol 16:378–391. https://doi.org/10.1038/NRI.2016.49 Declercq J, van Damme KFA, de Leeuw E et al (2021) Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial. Lancet Respir Med 9:1427–1438. https://doi.org/10.1016/S2213-2600(21)00377-5 Dehingia N, Raj A (2021) Sex differences in COVID-19 case fatality: do we know enough? Lancet Glob Health 9:e14–e15. https://doi.org/10.1016/S2214-109X(20)30464-2 Delorey TM, Ziegler CGK, Heimberg G et al (2021) A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2. bioRxiv. https://doi.org/10.1101/2021.02.25.430130 Distler O, Assassi S, Cottin V et al (2020) Predictors of progression in systemic sclerosis patients with interstitial lung disease. Eur Respir J. https://doi.org/10.1183/13993003.02026-2019 Dubový P, Hradilová-Svíženská I, Klusáková I et al (2019) Interleukin-6 contributes to initiation of neuronal regeneration program in the remote dorsal root ganglia neurons after sciatic nerve injury. Histochem Cell Biol 152:109–117. https://doi.org/10.1007/S00418-019-01779-3 Dubový P, Hradilová-Svíženská I, Brázda V, Joukal M (2021) Toll-like receptor 9-mediated neuronal innate immune reaction is associated with initiating a pro-regenerative state in neurons of the dorsal root ganglia non-associated with sciatic nerve lesion. Int J Mol Sci. https://doi.org/10.3390/IJMS22147446 Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. https://doi.org/10.1056/NEJM198612253152606 Dvořánková B, Szabo P, Lacina L et al (2011) Human galectins induce conversion of dermal fibroblasts into myofibroblasts and production of extracellular matrix: potential application in tissue engineering and wound repair. Cells Tissues Organs 194:469–480. https://doi.org/10.1159/000324864 Eelen G, Treps L, Li X, Carmeliet P (2020) Basic and therapeutic aspects of angiogenesis updated. Circ Res 127:310–329. https://doi.org/10.1161/CIRCRESAHA.120.316851 Ehrlich P (1900) Croonian lecture—on immunity with special reference to cell life. Proc R Soc Lond 66:424–448. https://doi.org/10.1098/RSPL.1899.0121 Ellis S, Lin EJ, Tartar D (2018) Immunology of wound healing. Curr Dermatol Rep 7:350–358. https://doi.org/10.1007/S13671-018-0234-9 Epstein Shochet G, Brook E, Bardenstein-Wald B, Shitrit D (2020) TGF-β pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling. Respir Res. https://doi.org/10.1186/S12931-020-1319-0 Evans RA, Tian YC, Steadman R, Phillips AO (2003) TGF-β1-mediated fibroblast-myofibroblast terminal differentiation – the role of Smad proteins. Exp Cell Res 282:90–100. https://doi.org/10.1016/S0014-4827(02)00015-0 Fakra E, Marotte H (2021) Rheumatoid arthritis and depression. Joint Bone Spine. https://doi.org/10.1016/J.JBSPIN.2021.105200 Ferreli C, Gasparini G, Parodi A et al (2017) Cutaneous manifestations of scleroderma and scleroderma-like disorders: a comprehensive review. Clin Rev Allergy Immunol 53:306–336. https://doi.org/10.1007/S12016-017-8625-4 Fertala J, Rivlin M, Wang ML et al (2020) Collagen-rich deposit formation in the sciatic nerve after injury and surgical repair: a study of collagen-producing cells in a rabbit model. Brain Behav. https://doi.org/10.1002/BRB3.1802 Franceschi C, Garagnani P, Parini P et al (2018) Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14:576–590. https://doi.org/10.1038/S41574-018-0059-4 Gajewski T, Rouhani S, Trujillo J et al (2021) Severe COVID-19 infection is associated with aberrant cytokine production by infected lung epithelial cells rather than by systemic immune dysfunction. Res Sq. https://doi.org/10.21203/RS.3.RS-1083825/V1 Genova C, Dellepiane C, Carrega P et al (2022) Therapeutic implications of tumor microenvironment in lung cancer: focus on immune checkpoint blockade. Front Immunol. https://doi.org/10.3389/FIMMU.2021.799455 Ghanem M, Homps-Legrand M, Garnier M et al (2021) Blood fibrocytes are associated with severity and prognosis in COVID-19 pneumonia. Am J Physiol Lung Cell Mol Physiol 321:L847–L858. https://doi.org/10.1152/AJPLUNG.00105.2021 Giacomelli C, Piccarducci R, Marchetti L et al (2021) Pulmonary fibrosis from molecular mechanisms to therapeutic interventions: lessons from post-COVID-19 patients. Biochem Pharmacol. https://doi.org/10.1016/J.BCP.2021.114812 Gray WK, Navaratnam AV, Day J et al (2021) COVID-19 hospital activity and in-hospital mortality during the first and second waves of the pandemic in England: an observational study. Thorax. https://doi.org/10.1136/THORAXJNL-2021-218025 Grazul-Bilska AT, Luthra G, Reynolds LP et al (2002) Effects of basic fibroblast growth factor (FGF-2) on proliferation of human skin fibroblasts in type II diabetes mellitus. Exp Clin Endocrinol Diabetes 110:176–181. https://doi.org/10.1055/S-2002-32149 Griffin MF, desJardins-Park HE, Mascharak S, et al (2020) Understanding the impact of fibroblast heterogeneity on skin fibrosis. Dis Model Mech. https://doi.org/10.1242/DMM.044164 Gupta S, Padappayil RP, Bansal A et al (2022) Tocilizumab in patients hospitalized with COVID-19 pneumonia: systematic review and meta-analysis of randomized controlled trials. J Investig Med 70:55–60. https://doi.org/10.1136/JIM-2021-002001 Hall DJ, Schulte JJ, Lewis EE et al (2021) Successful lung transplantation for severe post COVID-19 pulmonary fibrosis. Ann Thorac Surg. https://doi.org/10.1016/J.ATHORACSUR.2021.10.004 Henshaw FR, Dewsbury LS, Lim CK, Steiner GZ (2021) The effects of cannabinoids on pro- and anti-inflammatory cytokines: a systematic review of in vivo studies. Cannabis Cannabinoid Res 6:177–195. https://doi.org/10.1089/CAN.2020.0105 Hinz B (2016) The role of myofibroblasts in wound healing. Curr Res Transl Med 64:171–177. https://doi.org/10.1016/J.RETRAM.2016.09.003 Hirota H, Kiyama H, Kishimoto T, Taga T (1996) Accelerated nerve regeneration in mice by upregulated expression of interleukin (IL) 6 and IL-6 receptor after trauma. J Exp Med 183:2627–2634. https://doi.org/10.1084/JEM.183.6.2627 Hung CF, Rohani MG, Lee S Soon, et al (2013) Role of IGF-1 pathway in lung fibroblast activation. Respir Res https://doi.org/10.1186/1465-9921-14-102 Iorio GC, Ammendolia A, Marotta N et al (2021) A bond between rheumatic diseases and cancer in the elderly: the interleukin-6 pathway. Int J Rheum Dis 24:1317–1320. https://doi.org/10.1111/1756-185X.14194 Jarlborg M, Gabay C (2022) Systemic effects of IL-6 blockade in rheumatoid arthritis beyond the joints. Cytokine. https://doi.org/10.1016/J.CYTO.2021.155742 Jehn CF, Kühnhardt D, Bartholomae A et al (2010) Association of IL-6, hypothalamus-pituitary-adrenal axis function, and depression in patients with cancer. Integr Cancer Ther 9:270–275. https://doi.org/10.1177/1534735410370036 Jobe NP, Rösel D, Dvořánková B et al (2016) Simultaneous blocking of IL-6 and IL-8 is sufficient to fully inhibit CAF-induced human melanoma cell invasiveness. Histochem Cell Biol 146:205–217. https://doi.org/10.1007/S00418-016-1433-8 Jobe NP, Živicová V, Mifková A et al (2018) Fibroblasts potentiate melanoma cells in vitro invasiveness induced by UV-irradiated keratinocytes. Histochem Cell Biol 149:503–516. https://doi.org/10.1007/S00418-018-1650-4 Jones SA, Scheller J, Rose-John S (2011) Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 121:3375–3383. https://doi.org/10.1172/JCI57158 Kaffash Farkhad N, Reihani H, Sedaghat A et al (2021) Are mesenchymal stem cells able to manage cytokine storm in COVID-19 patients? A review of recent studies. Regen Ther 18:152–160. https://doi.org/10.1016/J.RETH.2021.05.007 Kalluri R (2016) The biology and function of fibroblasts in cancer. Nat Rev Cancer 16:582–598. https://doi.org/10.1038/nrc.2016.73 Kang S, Tanaka T, Narazaki M, Kishimoto T (2019) Targeting interleukin-6 signaling in clinic. Immunity 50:1007–1023. https://doi.org/10.1016/J.IMMUNI.2019.03.026 Karampoor S, Hesamizadeh K, Shams Z et al (2021) The role of lovastatin in the attenuation of COVID-19. Int Immunopharmacol. https://doi.org/10.1016/J.INTIMP.2021.108192 Karthika T, Joseph J, Akshay Das VR et al (2021) SARS-CoV-2 cellular entry is independent of the ACE2 cytoplasmic domain signaling. Cells. https://doi.org/10.3390/CELLS10071814 Kasprzak A (2021) The role of tumor microenvironment cells in colorectal cancer (CRC) cachexia. Int J Mol Sci 22:1–34. https://doi.org/10.3390/IJMS22041565 Katenkamp D, Stiller D (1978) Ultrastructure of perineurial cells during peripheral nerve regeneration. Electron microscopical investigations on the so-called amputation neuroma. Exp Pathol (Jena) 16:5–15. https://doi.org/10.1016/S0014-4908(78)80002-7 Kavianpour M, Saleh M, Verdi J (2020) The role of mesenchymal stromal cells in immune modulation of COVID-19: focus on cytokine storm. Stem Cell Res Ther. https://doi.org/10.1186/S13287-020-01849-7 Khanna D, Lin CJF, Furst DE et al (2020) Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 8:963–974. https://doi.org/10.1016/S2213-2600(20)30318-0 Kheirollahi V, Wasnick RM, Biasin V et al (2019) Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis. Nat Commun. https://doi.org/10.1038/S41467-019-10839-0 Kodet O, Kučera J, Strnadová K et al (2020) Cutaneous melanoma dissemination is dependent on the malignant cell properties and factors of intercellular crosstalk in the cancer microenvironment (review). Int J Oncol 57:619–630. https://doi.org/10.3892/IJO.2020.5090 Kolář M, Szabo P, Dvořánková B et al (2012) Upregulation of IL-6, IL-8 and CXCL-1 production in dermal fibroblasts by normal/malignant epithelial cells in vitro: Immunohistochemical and transcriptomic analyses. Biol Cell 104:738–751. https://doi.org/10.1111/BOC.201200018 Kruglikov IL, Scherer PE (2020) The role of adipocytes and adipocyte-like cells in the severity of COVID-19 infections. Obesity 28:1187–1190. https://doi.org/10.1002/OBY.22856 Kučera J, Strnadová K, Dvořánková B et al (2019) Serum proteomic analysis of melanoma patients with immunohistochemical profiling of primary melanomas and cultured cells: pilot study. Oncol Rep 42:1793–1804. https://doi.org/10.3892/OR.2019.7319 Lacina L, Kodet O, Dvořánková B et al (2018) Ecology of melanoma cell. Histol Histopathol 33:247–254. https://doi.org/10.14670/HH-11-926 Lacina L, Brábek J, Král V et al (2019) Interleukin-6: a molecule with complex biological impact in cancer. Histol Histopathol 34:125–136. https://doi.org/10.14670/HH-18-033 Lacina L, Brábek J, Fingerhutová Š et al (2021) Pediatric inflammatory multisystem syndrome (PIMS)—potential role for cytokines such Is IL-6. Physiol Res 70:153–159. https://doi.org/10.33549/PHYSIOLRES.934673 Lamontagne F, Agoritsas T, MacDonald H et al (2020) A living WHO guideline on drugs for COVID-19. BMJ. https://doi.org/10.1136/BMJ.M3379 Landén NX, Li D, Ståhle M (2016) Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci 73:3861–3885. https://doi.org/10.1007/S00018-016-2268-0 Leask A (2013) Focal adhesion kinase: a key mediator of transforming growth factor beta signaling in fibroblasts. Adv Wound Care 2:247–249. https://doi.org/10.1089/WOUND.2012.0363 Lerbs T, Cui L, King ME et al (2020) CD47 prevents the elimination of diseased fibroblasts in scleroderma. JCI Insight. https://doi.org/10.1172/JCI.INSIGHT.140458 Li B, Wang JHC (2011) Fibroblasts and myofibroblasts in wound healing: force generation and measurement. J Tissue Viability 20:108–120. https://doi.org/10.1016/J.JTV.2009.11.004 Li H, Yao Z, He W et al (2016) P311 induces the transdifferentiation of epidermal stem cells to myofibroblast-like cells by stimulating transforming growth factor β1 expression. Stem Cell Res Ther 7:1–17. https://doi.org/10.1186/S13287-016-0421-1 Li R, Wen A, Lin J (2020) Pro-inflammatory cytokines in the formation of the pre-metastatic niche. Cancers 12:1–16. https://doi.org/10.3390/CANCERS12123752 Li X, Guan Y, Li C et al (2022) Immunomodulatory effects of mesenchymal stem cells in peripheral nerve injury. Stem Cell Res Ther. https://doi.org/10.1186/S13287-021-02690-2 Lindborg JA, Niemi JP, Howarth MA et al (2018) Molecular and cellular identification of the immune response in peripheral ganglia following nerve injury. J Neuroinflammation. https://doi.org/10.1186/S12974-018-1222-5 Liu T, Han C, Wang S et al (2019) Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol. https://doi.org/10.1186/S13045-019-0770-1 Liu X, Rowan SC, Liang J et al (2021) Categorization of lung mesenchymal cells in development and fibrosis. iScience. https://doi.org/10.1016/J.ISCI.2021.102551 Ma Y, Dong L, Zhou D et al (2019) Extracellular vesicles from human umbilical cord mesenchymal stem cells improve nerve regeneration after sciatic nerve transection in rats. J Cell Mol Med 23:2822–2835. https://doi.org/10.1111/JCMM.14190 Macarak EJ, Wermuth PJ, Rosenbloom J, Uitto J (2021) Keloid disorder: fibroblast differentiation and gene expression profile in fibrotic skin diseases. Exp Dermatol 30:132–145. https://doi.org/10.1111/EXD.14243 Majidpoor J, Mortezaee K (2022) Interleukin-6 in SARS-CoV-2 induced disease: interactions and therapeutic applications. Biomed Pharmacother. https://doi.org/10.1016/J.BIOPHA.2021.112419 Mardani R, Namavar M, Ghorbi E et al (2022) Association between serum inflammatory parameters and the disease severity in COVID-19 patients. J Clin Lab Anal. https://doi.org/10.1002/JCLA.24162 Martinez-Guerra BA, Gonzalez-Lara MF, Roman-Montes CM et al (2022) Outcomes of patients with severe and critical COVID-19 treated with dexamethasone: a prospective cohort study. Emerg Microbes Infect 11:50–59. https://doi.org/10.1080/22221751.2021.2011619 Mateu R, Ẑivicová V, Krejí ED et al (2016) Functional differences between neonatal and adult fibroblasts and keratinocytes: donor age affects epithelial-mesenchymal crosstalk in vitro. Int J Mol Med 38:1063–1074. https://doi.org/10.3892/IJMM.2016.2706 Mehta P, Cron RQ, Hartwell J et al (2020) Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol 2:e358–e367. https://doi.org/10.1016/S2665-9913(20)30096-5 Molfino A, Iannace A, Colaiacomo MC et al (2017) Cancer anorexia: hypothalamic activity and its association with inflammation and appetite-regulating peptides in lung cancer. J Cachexia Sarcopenia Muscle 8:40–47. https://doi.org/10.1002/JCSM.12156 Mulder PPG, Vlig M, Boekema BKHL et al (2021) Persistent systemic inflammation in patients with severe burn injury is accompanied by influx of immature neutrophils and shifts in T cell subsets and cytokine profiles. Front Immunol. https://doi.org/10.3389/FIMMU.2020.621222 Müller L, di Benedetto S (2021) How immunosenescence and inflammaging may contribute to hyperinflammatory syndrome in COVID-19. Int J Mol Sci. https://doi.org/10.3390/IJMS222212539 Nestler T, Dalvi P, Haidl F et al (2022) Transcriptome analysis reveals upregulation of immune response pathways at the invasive tumour front of metastatic seminoma germ cell tumours. Br J Cancer 126:937–947. https://doi.org/10.1038/S41416-021-01621-5 Niemi JP, DeFrancesco-Lisowitz A, Cregg JM et al (2016) Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism. Exp Neurol 275(Pt 1):25–37. https://doi.org/10.1016/J.EXPNEUROL.2015.09.018 Nurmik M, Ullmann P, Rodriguez F et al (2020) In search of definitions: cancer-associated fibroblasts and their markers. Int J Cancer 146:895–905. https://doi.org/10.1002/IJC.32193 Nyika DT, Khumalo NP, Bayat A (2022) Genetics and epigenetics of keloids. Adv Wound Care 11:192–201. https://doi.org/10.1089/WOUND.2021.0094 Oliveira KMC, Pindur L, Han Z et al (2018) Time course of traumatic neuroma development. PLoS ONE. https://doi.org/10.1371/JOURNAL.PONE.0200548 Ollewagen T, Myburgh KH, van de Vyver M, Smith C (2021) Rheumatoid cachexia: the underappreciated role of myoblast, macrophage and fibroblast interplay in the skeletal muscle niche. J Biomed Sci. https://doi.org/10.1186/S12929-021-00714-W Paccagnella M, Abbona A, Michelotti A et al (2022) Circulating cytokines in metastatic breast cancer patients select different prognostic groups and patients who might benefit from treatment beyond progression. Vaccines. https://doi.org/10.3390/VACCINES10010078 Pallangyo CK, Ziegler PK, Greten FR (2015) IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis. J Exp Med 212:2253–2266. https://doi.org/10.1084/JEM.20150576 Pannell M, Labuz D, Celik M et al (2016) Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides. J Neuroinflammation. https://doi.org/10.1186/S12974-016-0735-Z Parimoo A, Biswas A, Baitha U et al (2021) Dynamics of inflammatory markers in predicting mortality in COVID-19. Cureus. https://doi.org/10.7759/CUREUS.19080 Park SA, Kim LK, Park HM et al (2022) Inhibition of GP130/STAT3 and EMT by combined bazedoxifene and paclitaxel treatment in ovarian cancer. Oncol Rep. https://doi.org/10.3892/OR.2022.8263 Pastar I, Stojadinovic O, Yin NC et al (2014) Epithelialization in wound healing: a comprehensive review. Adv Wound Care 3:445–464. https://doi.org/10.1089/WOUND.2013.0473 Patil S, Testarelli L (2021) Assessment of growth factors, cytokines, and cellular markers in saliva of patients with trigeminal neuralgia. Molecules. https://doi.org/10.3390/MOLECULES26102964 Patsalos O, Dalton B, Himmerich H (2020) Effects of IL-6 signaling pathway inhibition on weight and BMI: a systematic review and meta-analysis. Int J Mol Sci 21:1–13. https://doi.org/10.3390/IJMS21176290 Paval DR, Patton R, McDonald J et al (2022) A systematic review examining the relationship between cytokines and cachexia in incurable cancer. J Cachexia Sarcopenia Muscle. https://doi.org/10.1002/JCSM.12912 Pedersen SF, Ho YC (2020) SARS-CoV-2: a storm is raging. J Clin Invest 130:2202–2205. https://doi.org/10.1172/JCI137647 Pedroza M, Schneider DJ, Karmouty-Quintana H et al (2011) Interleukin-6 contributes to inflammation and remodeling in a model of adenosine mediated lung injury. PLoS ONE. https://doi.org/10.1371/JOURNAL.PONE.0022667 Pettersen K, Andersen S, Degen S et al (2017) Cancer cachexia associates with a systemic autophagy-inducing activity mimicked by cancer cell-derived IL-6 trans-signaling. Sci Rep. https://doi.org/10.1038/S41598-017-02088-2 Piera-Velazquez S, Li Z, Jimenez SA (2011) Role of endothelial–mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am J Pathol 179:1074–1080. https://doi.org/10.1016/J.AJPATH.2011.06.001 Plzák J, Bouček J, Bandúrová V et al (2019) The head and neck squamous cell carcinoma microenvironment as a potential target for cancer therapy. Cancers. https://doi.org/10.3390/CANCERS11040440 Pollini M, Paladini F (2020) Bioinspired materials for wound healing application: the potential of silk fibroin. Materials 13:3361. https://doi.org/10.3390/MA13153361 Popper H, Stacher-Priehse E, Brcic L, Nerlich A (2021) Lung fibrosis in autoimmune diseases and hypersensitivity: how to separate these from idiopathic pulmonary fibrosis. Rheumatol Int. https://doi.org/10.1007/S00296-021-05002-2 Quan TE, Cowper SE, Bucala R (2006) The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep 8:145–150. https://doi.org/10.1007/S11926-006-0055-X Ramirez AM, Shen Z, Ritzenthaler JD, Roman J (2006) Myofibroblast transdifferentiation in obliterative bronchiolitis: TGF-β signaling through smad3-dependent and -independent pathways. Am J Transplant 6:2080–2088. https://doi.org/10.1111/J.1600-6143.2006.01430.X Rao PN, Mainkar O, Bansal N et al (2021) Flavonoids in the treatment of neuropathic pain. Curr Pain Headache Rep. https://doi.org/10.1007/S11916-021-00959-Y Rea IM, Gibson DS, McGilligan V et al (2018) Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol. https://doi.org/10.3389/FIMMU.2018.00586 Rehan VK, Torday JS (2003) Hyperoxia augments pulmonary lipofibroblast-to-myofibroblast transdifferentiation. Cell Biochem Biophys 38:239–249. https://doi.org/10.1385/CBB:38:3:239 Rehan VK, Torday JS (2014) The lung alveolar lipofibroblast: an evolutionary strategy against neonatal hyperoxic lung injury. Antioxid Redox Signal 21:1893–1904. https://doi.org/10.1089/ARS.2013.5793 Reinke JM, Sorg H (2012) Wound repair and regeneration. Eur Surg Res 49:35–43. https://doi.org/10.1159/000339613 Rezaei F, Mozaffari HR, Tavasoli J et al (2019) Evaluation of serum and salivary interleukin-6 and interleukin-8 levels in oral squamous cell carcinoma patients: systematic review and meta-analysis. J Interferon Cytokine Res 39:727–739. https://doi.org/10.1089/JIR.2019.0070 Rosa JS, Flores RL, Oliver SR et al (2008) Sustained IL-1alpha, IL-4, and IL-6 elevations following correction of hyperglycemia in children with type 1 diabetes mellitus. Pediatr Diabetes 9:9–16. https://doi.org/10.1111/J.1399-5448.2007.00243.X Rose-John S (2012) IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci 8:1237–1247. https://doi.org/10.7150/IJBS.4989 Rossi F, di Paola A, Pota E et al (2021) Biological aspects of inflamm-aging in childhood cancer survivors. Cancers. https://doi.org/10.3390/CANCERS13194933 Saikia P, Crabb JS, Dibbin LL et al (2020) Quantitative proteomic comparison of myofibroblasts derived from bone marrow and cornea. Sci Rep. https://doi.org/10.1038/S41598-020-73686-W Santoft F, Hedman-Lagerlöf E, Salomonsson S et al (2020) Inflammatory cytokines in patients with common mental disorders treated with cognitive behavior therapy. Brain Behav Immun Health 3:100045. https://doi.org/10.1016/J.BBIH.2020.100045 Santoro A, Bientinesi E, Monti D (2021) Immunosenescence and inflammaging in the aging process: age-related diseases or longevity? Ageing Res Rev. https://doi.org/10.1016/J.ARR.2021.101422 Schuster R, Rockel JS, Kapoor M, Hinz B (2021) The inflammatory speech of fibroblasts. Immunol Rev 302:126–146. https://doi.org/10.1111/IMR.12971 Shao Y, Chen T, Zheng X et al (2018) Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis. Carcinogenesis 39:1368–1379. https://doi.org/10.1093/CARCIN/BGY115 Shima Y, Kuwahara Y, Murota H et al (2010) The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology 49:2408–2412. https://doi.org/10.1093/RHEUMATOLOGY/KEQ275 Smetana K, Brábek J (2020) Role of interleukin-6 in lung complications in patients with COVID-19: therapeutic implications. In Vivo 34:1589–1592. https://doi.org/10.21873/INVIVO.11947 Smetana K, Lacina L, Szabo P et al (2016) Ageing as an important risk factor for cancer. Anticancer Res 36:5009–5017. https://doi.org/10.21873/ANTICANRES.11069 Smetana K, Lacina L, Kodet O (2020a) Targeted therapies for melanoma. Cancers 12:1–4. https://doi.org/10.3390/CANCERS12092494 Smetana K, Rosel D, Brábek J (2020b) Raloxifene and bazedoxifene could be promising candidates for preventing the COVID-19 related cytokine storm, ARDS and mortality. In Vivo 34:3027–3028. https://doi.org/10.21873/INVIVO.12135 Song D, Yu W, Ren Y et al (2020) Discovery of bazedoxifene analogues targeting glycoprotein 130. Eur J Med Chem 199:112375. https://doi.org/10.1016/J.EJMECH.2020.112375 Španko M, Strnadová K, Pavlíček AJ et al (2021) IL-6 in the ecosystem of head and neck cancer: possible therapeutic perspectives. Int J Mol Sci. https://doi.org/10.3390/IJMS222011027 Strnadová K, Pfeiferová L, Přikryl P et al (2022) Exosomes produced by melanoma cells significantly influence the biological properties of normal and cancer-associated fibroblasts. Histochem Cell Biol 157:153–172. https://doi.org/10.1007/S00418-021-02052-2 Takahashi T, Iwasaki A (2021) Sex differences in immune responses. Science 371:347–348. https://doi.org/10.1126/SCIENCE.ABE7199 Te Lin Y, Chen JS, Wu MH et al (2015) Galectin-1 accelerates wound healing by regulating the neuropilin-1/Smad3/NOX4 pathway and ROS production in myofibroblasts. J Invest Dermatol 135:258–268. https://doi.org/10.1038/JID.2014.288 Thiery JP, Acloque H, Huang RYJ, Nieto MA (2009) Epithelial–mesenchymal transitions in development and disease. Cell 139:871–890. https://doi.org/10.1016/J.CELL.2009.11.007 Thulabandu V, Chen D, Atit RP (2018) Dermal fibroblast in cutaneous development and healing. Wiley Interdiscip Rev Dev Biol. https://doi.org/10.1002/WDEV.307 Tracy LE, Minasian RA, Caterson EJ (2016) Extracellular matrix and dermal fibroblast function in the healing wound. Adv Wound Care 5:119–136. https://doi.org/10.1089/WOUND.2014.0561 Trylcova J, Busek P, Smetana K et al (2015) Effect of cancer-associated fibroblasts on the migration of glioma cells in vitro. Tumour Biol 36:5873–5879. https://doi.org/10.1007/S13277-015-3259-8 Urch CE, Dickenson AH (2008) Neuropathic pain in cancer. Eur J Cancer 44:1091–1096. https://doi.org/10.1016/J.EJCA.2008.03.015 Ushakumary MG, Riccetti M, Perl AKT (2021) Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration. Stem Cells Transl Med 10:1021–1032. https://doi.org/10.1002/SCTM.20-0526 Valdebenito S, Bessis S, Annane D et al (2021) COVID-19 lung pathogenesis in SARS-CoV-2 autopsy cases. Front Immunol. https://doi.org/10.3389/FIMMU.2021.735922 van Caam A, Vonk M, van den Hoogen F et al (2018) Unraveling SSc pathophysiology; the myofibroblast. Front Immuno. https://doi.org/10.3389/FIMMU.2018.02452 van Praet JT, Smith V, Haspeslagh M et al (2011) Histopathological cutaneous alterations in systemic sclerosis: a clinicopathological study. Arthritis Res Ther. https://doi.org/10.1186/AR3267 Vokurka M, Lacina L, Brábek J et al (2022) Cancer-associated fibroblasts influence the biological properties of malignant tumours via paracrine secretion and exosome production. Int J Mol Sci. https://doi.org/10.3390/IJMS23020964 Vorstandlechner V, Laggner M, Kalinina P et al (2020) Deciphering the functional heterogeneity of skin fibroblasts using single-cell RNA sequencing. FASEB J 34:3677–3692. https://doi.org/10.1096/FJ.201902001RR Wang ML, Rivlin M, Graham JG, Beredjiklian PK (2019) Peripheral nerve injury, scarring, and recovery. Connect Tissue Res 60:3–9. https://doi.org/10.1080/03008207.2018.1489381 Wang Y, Ramachandran V, Sui D et al (2021) Evaluation of plasma IL-6 in patients with melanoma as a prognostic and checkpoint immunotherapy predictive biomarker. J Invest Dermatol. https://doi.org/10.1016/J.JID.2021.12.012 Wendisch D, Dietrich O, Mari T et al (2021) SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell 184:6243-6261.e27. https://doi.org/10.1016/J.CELL.2021.11.033 White JP (2017) IL-6, cancer and cachexia: metabolic dysfunction creates the perfect storm. Transl Cancer Res 6:S280–S285. https://doi.org/10.21037/TCR.2017.03.52 Wilgus TA (2020) Inflammation as an orchestrator of cutaneous scar formation: a review of the literature. Plast Aesthet Res. https://doi.org/10.20517/2347-9264.2020.150 Wofford KL, Shultz RB, Burrell JC, Cullen DK (2022) Neuroimmune interactions and immunoengineering strategies in peripheral nerve repair. Prog Neurobiol. https://doi.org/10.1016/J.PNEUROBIO.2021.102172 Wokalek H, Ruh H (1991) Time course of wound healing. J Biomater Appl 5:337–362. https://doi.org/10.1177/088532829100500405 Wolf J, Rose-John S, Garbers C (2014) Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine 70:11–20. https://doi.org/10.1016/J.CYTO.2014.05.024 Wong CE, Paratore C, Dours-Zimmermann MT et al (2006) Neural crest-derived cells with stem cell features can be traced back to multiple lineages in the adult skin. J Cell Biol 175:1005–1015. https://doi.org/10.1083/JCB.200606062 Wood NR, Garritson J, Mathias A et al (2022) Moderate intensity endurance and resistance exercise attenuates cachexia in tumor-bearing mice. Anticancer Res 42:397–405. https://doi.org/10.21873/ANTICANRES.15498 Wu H, Yu Y, Huang H et al (2020) Progressive pulmonary fibrosis is caused by elevated mechanical tension on alveolar stem cells. Cell 180:107-121.e17. https://doi.org/10.1016/J.CELL.2019.11.027 Wu MA, Lopez G, Nebuloni M et al (2021) Lung histopathologic clusters in severe COVID-19: a link between clinical picture and tissue damage. Crit Care. https://doi.org/10.1186/S13054-021-03846-5 Xie W, Strong JA, Zhang JM (2017) Active nerve regeneration with failed target reinnervation drives persistent neuropathic pain. eNeuro. https://doi.org/10.1523/ENEURO.0008-17.2017 Xu J, Ye Y, Zhang H et al (2016) Diagnostic and prognostic value of serum interleukin-6 in colorectal cancer. Medicine. https://doi.org/10.1097/MD.0000000000002502 Xu K, Wei Y, Giunta S et al (2021) Do inflammaging and coagul-aging play a role as conditions contributing to the co-occurrence of the severe hyper-inflammatory state and deadly coagulopathy during COVID-19 in older people? Exp Gerontol. https://doi.org/10.1016/J.EXGER.2021.111423 Yan H, Gao W, Pan Z et al (2012) The expression of α-SMA in the painful traumatic neuroma: potential role in the pathobiology of neuropathic pain. J Neurotrauma 29:2791–2797. https://doi.org/10.1089/NEU.2012.2502 Yaqoub L, Elgendy IY, Pepine CJ (2021) Sex and gender differences in COVID-19: more to be learned! Am Heart J Plus 3:100011. https://doi.org/10.1016/J.AHJO.2021.100011 Yeh CF, Li WY, Chu PY et al (2016) Pretreatment pain predicts perineural invasion in oral squamous cell carcinoma: a prospective study. Oral Oncol 61:115–119. https://doi.org/10.1016/J.ORALONCOLOGY.2016.07.016 Yehia R, Schaalan M, Abdallah DM et al (2021) Impact of TNF-α gene polymorphisms on pancreatic and non-small cell lung cancer-induced cachexia in adult Egyptian patients: a focus on pathogenic trajectories. Front Oncol. https://doi.org/10.3389/FONC.2021.783231 Yi M, Zheng X, Niu M et al (2022) Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer. https://doi.org/10.1186/S12943-021-01489-2 Yip RML, Yim CW (2021) Role of interleukin 6 inhibitors in the management of rheumatoid arthritis. J Clin Rheumatol 27:E516–E524. https://doi.org/10.1097/RHU.0000000000001293 Zhang L, Zhao Y, Lu Y et al (2020a) Effects of vacuum sealing drainage to improve the therapeutic effect in patients with orthopedic trauma and to reduce post-operative infection and lower-limb deep venous thrombosis. Exp Ther Med. https://doi.org/10.3892/ETM.2020.8941 Zhang T, Wang XF, Wang ZC et al (2020b) Current potential therapeutic strategies targeting the TGF-β/Smad signaling pathway to attenuate keloid and hypertrophic scar formation. Biomed Pharmacother. https://doi.org/10.1016/J.BIOPHA.2020.110287 Zhang R, Roque DM, Reader J, Lin J (2022) Combined inhibition of IL-6 and IL-8 pathways suppresses ovarian cancer cell viability and migration and tumor growth. Int J Oncol. https://doi.org/10.3892/IJO.2022.5340 Zhou YQ, Liu Z, Liu ZH et al (2016) Interleukin-6: an emerging regulator of pathological pain. J Neuroinflammation. https://doi.org/10.1186/S12974-016-0607-6 Ziegler CGK, Allon SJ, Nyquist SK et al (2020) SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 181:1016-1035.e19. https://doi.org/10.1016/J.CELL.2020.04.035 Zigmond RE, Echevarria FD (2019) Macrophage biology in the peripheral nervous system after injury. Prog Neurobiol 173:102–121. https://doi.org/10.1016/J.PNEUROBIO.2018.12.001 Živicová V, Lacina L, Mateu R et al (2017) Analysis of dermal fibroblasts isolated from neonatal and child cleft lip and adult skin: Developmental implications on reconstructive surgery. Int J Mol Med 40:1323–1334. https://doi.org/10.3892/IJMM.2017.3128 Zou X, Chen K, Zou J et al (2020) Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 14:185–192. https://doi.org/10.1007/S11684-020-0754-0