Fibroblasts are present in all tissues but predominantly in connective tissues. Some of their functions include contractility, locomotion, collagen and elastin fiber production, and the regulation and degradation of the extracellular matrix. Also, fibroblasts act as sentinels to produce inflammatory mediators in response to several microorganisms. There is evidence that fibroblasts can synthesize toll-like receptors (TLRs), antimicrobial peptides, proinflammatory cytokines, chemokines, and growth factors, which are important molecules involved in innate immune response against microorganisms. Fibroblasts can express TLRs (TLR-1 to TLR-10) to sense microbial components or microorganisms. They can synthesize antimicrobial peptides, such as LL-37, defensins hBD-1, and hBD-2, molecules that perform antimicrobial activity. Also, they can produce proinflammatory cytokines, such as TNFα, INFγ, IL-6, IL-12p70, and IL-10; other chemokines, such as CCL1, CCL2, CCL5, CXCL1, CXCL8, CXCL10, and CX3CL1; and the growth factors granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) to induce and recruit inflammatory cells. According to their immunological attributes, we can conclude that fibroblasts are sentinel cells that recognize pathogens, induce the recruitment of inflammatory cells via cytokines and growth factors, and release antimicrobial peptides, complying with the characteristics of real sentinels.
Delves PJ , Martin SM, Burton DR, Roitt IM (2014): Inmunología Fundamentos. 12th ed. Panamericana, Mexico
Jakab L : Connective tissue and inflammation. Orv Hetil 155, 453–460 (2014)
Kendall RT , Feghali-Bostwick CA: Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol 5, 1–13 (2014)
Abercrombie M : Fibroblasts. J Clin Pathol Suppl (R Coll Pathol) 12, 1–6 (1978)
Acosta A : El fibroblasto: su origen, estructura, funciones y heterogeneidad dentro del pediodonto. Univ Odontol 25, 26–33 (2006)
Jordana Särnstrand B , Sime PJ, Ramis I: Immune-inflammatory functions of fibroblasts. Eur Respir J 12, 2212–2222 (1994)
Xi X , McMillan DH, Leahmann GM, Sime PJ, Libby RT, Huxlin KR, Feldon SE, Phipps RP: Ocular fibroblasts diversity: implications for inflammation and ocular wound healing. Invest Ophthalmol Vis Sci 52, 4859–4865 (2011)
Palm E , Khalaf, Bengtsson T: Porphyromonas gingivalis downregulates the immune response of fibroblasts. BMC Microbiol 13, 1–9 (2013)
Armant MA , Fenton MJ: Toll-like receptors: a family of pattern-recognition receptors in mammals. Genome Biol 3, 1–6 (2002)
Winkler P . Ghadimi D, Scherezenmeir J, Kraerhenbuhl JP: Molecular and cellular basis of microflora–host interactions. J Nutr 137, 756S–72S (2007)
Pietracola G , Arciola CR, Rindi S, Di Poto, Missineo A, Montanaro L, Speziale P: Toll-Like receptors in innate immune defense against Staphylococcus aureus. Int J Artif Organs 34, 799–810 (2011)
Kumagai Y , Akira S: Identification and functions of pattern-recognition receptors. J Allergy Clin Immunol 125, 985–992 (2010)
Nagashima H , Iwatani S, Cruz M, Jiménez Abreu JA, Uchiha T, Mahachai V, Vilaichone RK, Graham DY, Yamaoka Y: Toll like receptor 10 in Helicobacter pylori infection. J Infect Dis 212, 1666–1676 (2015)
Yao C , Oh JH, Lee DH, Bae JS, Jin CL, Park CH, Chung JH: Toll-like receptor family members in skin fibroblasts are functional and have a higher expression compared to skin keratinocytes. Int J Mol Med 35, 1443–1450 (2015)
Guez-Martínez SR , Sanchez-Zauco NA, González-Ramirez I, Cancino-Díaz JC, Cancino-Diaz ME: Peptidoglycan from Staphylococcus aureus induces the overexpression of TLRs 1-8 mRNA in corneal fibroblasts, but its lipoteichoic acid and muramyl dipeptide only induced overexpression of TLR5 or TLR9. Braz J Microbiol 42, 1056–1060 (2011)
Herath TD , Darveau RP, Seneviratne CJ, Wang CY, Wang Y, Jin L: Tetra- and penta-acylated lipid A structures of Porphyromonas gingivalis LPS differentially activate TLR4-mediated NF-κB signal transduction cascade and immuno-inflammatory response in human gingival fibroblasts. PLoS One, 8:e58496 (2013)
Mahanonda R , Sa-Ard-Iam N, Montreekachon P, Pimkhaokham A, Yongvanichit K, Fukuda MM, Pichyangkul S: IL-8 and IDO expression by human gingival fibroblasts via TLRs. Immunol 178, 1151–1157 (2007)
Wong Y , Sethu C, Louafi, Hossain P: Lipoplysaccharide regulation of toll-like receptor-4 and matrix metalloprotease-9 in human primary corneal fibroblasts. Invest Ophthalmol Vis Sci 52, 2796–2803 (2011)
Obermeier F , Strauch UG, Dunger N, Grunwald N, Rath HC, Herfarth H, Schölmerich J, Falk W: In vivo CpG DNA/toll-like receptor 9 interaction induces regulatory properties in CD4+CD62L+ T cells which prevent intestinal inflammation in the SCID transfer model of colitis. Gut 54, 1428–1436 (2005)
Kyburz D , Rethage J, Seibl R, Lauener R, Gay RE, Carson DA, Gay S: Bacterial peptidoglycans but not CpG oligodeoxynucleotides activate synovial fibroblasts by toll-like receptor signaling. Arthritis Rheum 48, 642–650 (2003)
Guo H , Wu X, Yu FS, Zhao J: Toll-like receptor 2 mediates the induction of IL-10 in corneal fibroblasts in response to Fusarium solu. Immunol Cell Biol 86:271–276 (2008)
Jie Zhao , Wu XY, Yu FS: Activation of Toll-like receptors 2 and 4 in Aspergillus fumigatus Keratitis. Innate Immun 15, 155–168 (2009)
Domínguez-Lopez A , Bautista-de Lucio VM, Serafín-Lopez J, Robles-Sanches E, Garfias Y: Amniotic membrane modulates innate immune response inhibiting PRRs expression and NF-kB nuclear translocation on limbal myofibroblasts. Exp Eye Resp 127, 215–223 (2014)
Farina GA , York MR, Di Marzio M, Collins CA, Meller S, Hommey B, Rifkin IR, Marshak-Rothstein A, Radstke TR, Lafyatis R: Poly(I:C) drives type I INF- and TGFβ-mediated inflammation and dermal fibrosis simulating altered gene expression in systemic sclerosis. J Invest Dermatol 130, 2583–2593 (2010)
Hans M , Madaan Hans V: Epithelial antimicrobial peptides: guardian of the oral cavity. Int J Pept, 370297 (2014)
Noore J , Noore A, Li B: Cationic antimicrobial peptide LL-37 is effective against both extra- and intracellular Staphylococcus aureus. Antimicrob Agents Chemother 57, 1283–1290 (2013)
Nielsen KL , Dynesen P, Larsen P, Jakobsen L, Andersen PS, Frimodt-Møller N: Role urinary cathelicidin LL-37 and human B-defensin 1 in uncomplicated Escherichia coli urinary tract infections. Infect Immune 82, 1572–1578 (2014)
Huang Q , Fei J, Yu HJ, Gou YB, Huang XK: Effects of human β-defensin-3 on biofilm formation-regulating genes dltB and icaA in Staphylococcus aureus. Mol Med Resp 10, 825–831 (2014)
Huang LC , Jean D, Proske RJ, Reins RY, McDermott AM: Ocular surface expression and in vitro activity of antimicrobial peptides. Curr Eye Res 32, 595–609 (2007)
Castañeda-Sanchez JI , García-Pérez BE, Muñoz-Duarte AR, Baltierra-Uribe SL, Mejia-López C, López-López C, Bautista-De Lucio VM, Robles-Contreras A, Luna-Herrera J: Defensin production by human limbo-corneal fibroblasts infected with mycobacteria. Pathogens 2, 13–32 (2013)
Rizzo A , Polillo R, Buommino E, Lanza AG, Guinda L, Annuziata M, Carratelli CR: Modulation of cytokine and beta-defensin 2 expressions in human gingival fibroblasts infected with Chlamydia pneumoniae. Int Immunopharmacol 8, 1239–1247 (2008)
Rodriguez-Martínez S , Cancino-Diaz M, Cancino-Diaz J: Expression of CRAMP via PNG-TLR-2 and of alpha-defensin-3 via CpG-ODN-TLR-9 in corneal fibroblast. Br J Ophthalmol 90, 378–382 (2006)
Abbas AK , Lichtman AP (2004): Inmunología Celular y Molecular. 5th ed. Elsevier, España
Lei D , Lancaster JR Jr, Joshi MS, Nelson S, Stoltz D, Bagby GJ, Odom G, Shellito JE, Kolls JK: Activation of alveolar macrophages and lung host defenses using transfer of the interferon-gamma gene. Am J Physiol 272, L852–859 (1997)
Mata-Espinosa DA , Hernández-Pando R: Interferón gamma: aspectos básicos, importancia clínica y usos terapéuticos. Rev Investigación Clin, 60, 421–431 (2008)
Tanaka T , Kishimoto T: The biology and medical implications of interleukin-6. Cancer Immunol Res 2, 288–294 (2014)
Maeda Y , Mukai T, Spencer J, Makino M: Identification of an immunomodulating agent from Mycobacterium leprae. Infect Immun 73, 2744–2750 (2005)
Kirker KR , James GA, Fleckman P, Orelund JE, Stewart PS: Differential effects of planktonic and biofilm MRSA on human fibroblasts. Wound Repair Regen 20, 253–261 (2012)
Dongari-Bagtzoglou A , Wen K, Lamster IB: Candida albicans triggers interleukin-6 and interleukin-8 responses by oral fibroblasts in vitro. Oral Microbiol Immunol 14, 364–370 (1999)
Falfán VR : Factor de necrosis tumoral: actividad biológica en neumopatías intersticiales. Rev Inst Nal Enf Resp Mex 15, 48–53 (2002)
Ioannidis LJ , Nie CQ, Hansen DS: The Role of chemokines in severe malaria: more than meets the eye. Parasitology 141, 602–613 (2014)
Sahingur SE , Yeudall WA: Chemokine function in periodontal disease and oral cavity cancer. Front Immunol 6, 1–15 (2015)
Oslund KL , Zhou X, Lee B, Zhu L, Duong T, Shih R, Baumgarth N, Hung LY, WU R, Chen Y: Synergistic upregulation of CXCL10 by virus and INF γ in human airway epithelial cells. PLoS One 9, e100978 (2014)
Chen J , Lau YF, Lamirande EW, Paddock CD, Bartlett JH, Zaki SR, Subbarao K: Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV. J Virol 84, 1289–1301 (2010)
Cursiefen C , Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D’Amore PA, Dana MR, Wiegand SJ, Streilein JW: VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113, 1040–1050 (2004)
Yuan X , Wilhelmus KR: Corneal neovascularization during experimental fungal keratitis. Mol Vis 15, 1988–1996 (2009)
Martins A , Han J, Kim SO: The multifaceted effects of granulocyte colony-stimulating factor in immunomodulating and potential roles in intestinal immune homeostasis. IUBMB Life 62, 611–617 (2010)
Shi Y , Liu CH, Roberts Al, Das J, Xu G, Ren G, Zhang ZR, Tan HS, Das G, Devadas S: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: What we do and don’t know. Cell Res 16, 126–133 (2006)
Lu Y , Liu Y, Fukuda K, Nakamura Y, Kumagai N, Nishida T: Inhibition by triptolide of chemokine, proinflammatory cytokine, and adhesion molecule expression induced by lipopolysaccharide in corneal fibroblasts. Invest Ophthalmol Vis Sci 47, 3796–3800 (2006)