Fibroblasts: the unknown sentinels eliciting immune responses against microorganisms

Abstract

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.

Origin and functional heterogeneity of fibroblasts

“…These balancing events may however produce overshoots, manifested by sustained and unwanted fibroblast activity and chronic inflammation in affected tissue. The fibroblast‐immune crosstalk has been the focus of other reviews and will only be discussed here with respect to novel approaches aimed to dissect the rate limiting functions of fibroblasts on innate and adaptive immune reactions.…”

“…Beyond the secretome, fibroblasts also engage the immune system through their expression of TLRs (toll‐like receptors) and production of antimicrobials such as defensins, possibly acting as sentinels in various organs such as the skin and lung (reviewed in ). The expression of TLRs by synovial fibroblasts may also be implicated in the chronic inflammatory responses associated with rheumatoid arthritis .…”

T Cell Proliferation Is Induced by Chronically TLR2-Stimulated Gingival Fibroblasts or Monocytes

“…Studies have also shown that CD14 ( [6,25], and this study) as well as TLR2 and TLR4 are expressed on human GFs and, thus, mediate pathogen interactions with GFs. Liu et al (2015) exposed a monocytic cell line to a TLR4 agonist, which enhanced the expression of adherence genes LFA-1 and VLA-4, suggesting that binding of monocytes to fibroblasts is likely partly regulated by LFA-1 and VLA-4 [26,27].…”

Manning the Barricades: Lung Fibroblasts and CD4+ T Cells as the Last Line of Defense against Bacterial Invasion?

“…Fibroblasts can themselves respond to both bacterial and viral infection as they express numerous PRRs, such as the Toll-like receptors. 42 Thus, fibroblasts can be activated either as a result of infection or in response to PAMPs such as LPS, poly(I:C) and flagellin. A common response to such innate stimuli is the release of soluble factors such as the potent neutrophil chemotactic factors CXCL8, as well as CXCL10 and CCL2, demonstrating a general ability to recruit innate responder cells in response to stimulation.…”