Role of TLR4 Receptor Complex in the Regulation of the Innate Immune Response by Fibronectin

Abstract

Chronic inflammation and subsequent tissue fibrosis are associated with a biochemical and mechanical remodeling of the fibronectin matrix. Due to its conformational lability, fibronectin is considerably stretched by the contractile forces of the fibrotic microenvironment, resulting in the unfolding of its Type III domains. In earlier studies, we have shown that a peptide mimetic of a partially unfolded fibronectin Type III domain, FnIII-1c, functions as a Damage Associated Molecular Pattern (DAMP) molecule to induce activation of a toll-like receptor 4 (TLR4)/NF-κB pathway and the subsequent release of fibro-inflammatory cytokines from human dermal fibroblasts. In the current study, we evaluated the requirement of the canonical TLR4/MD2/CD14 receptor complex in the regulation of FnIII-1c induced cytokine release. Using dermal fibroblasts and human embryonic kidney (HEK) cells, we found that all the components of the TLR4/MD2/CD14 complex were required for the release of the fibro-inflammatory cytokine, interleukin 8 (IL-8) in response to both FnIII-1c and the canonical TLR4 ligand, lipopolysaccharide (LPS). However, FnIII-1c mediated IL-8 release was strictly dependent on membrane-associated CD14, while LPS could use soluble CD14. These findings demonstrate that LPS and FnIII-1c share a similar but not identical mechanism of TLR4 activation in human dermal fibroblasts.

Non-celiac wheat sensitivity: rationality and irrationality of a gluten-free diet in individuals affected with non-celiac disease: a review

“…Although different polymorphisms of Toll-like receptor 4 (TLR4) have not been found in celiac disease [ 119 ], it seems that the TLR4-MD2-CD14 complex may be a potent activator of innate immune responses in monocytes, macrophages, and dendritic cells through Toll-like receptors and may play a role in NCWS [ 60 , 120 , 121 ]. MD2 is a secreted protein that interacts with TLR4, binds the lipid A moiety of lipopolysaccharides, and facilitates the creation of TLR4 dimers that are intimately required for downstream signaling and activation of the NF-κB (nuclear factor kappa light chain enhancer of activated B cells) pathway, while CD14 is a glycosyl-phosphatidylinositol (GPI)-linked protein found on the cell membrane in lipid rafts (microdomains at the plasmatic membrane with definite lipid and protein composition) and functions to transfer lipopolysaccharides from the bacterial cell wall to the MD2/TLR4 complex [ 122 ].…”

Mechanobiological Principles Influence the Immune Response in Regeneration: Implications for Bone Healing

“…Whether these higher fibronectin levels contribute to the osteoporotic pathology via immunomodulatory mechanisms, has not yet been fully elucidated. However, lung cells and dermal fibroblasts have been shown to bind the stretched fibronectin conformation via TLR4, which led to increased IL-8 levels (Cho et al, 2020;Zheng et al, 2020). Since IL-8 also seems to play an important role in bone healing (Lin et al, 2019), mechanical manipulation of the fibronectin conformation may also be an attractive therapeutic target (Figure 5B).…”

“…Another important ECM component that converts mechanical stimuli into an inflammatory response is fibronectin. Dermal fibroblasts have been shown to recognize stretched fibronectin as damage associated molecular patterns (DAMPs), which leads via the TLR4/NF-κB pathway to increased IL-8 expression (Zheng et al, 2020) (Figure 4C). Moreover, stretched fibronectin showed a higher binding affinity for IL-,7 and local accumulation of IL-7 may play an important role in the regulation of the immune response (Ortiz Franyuti et al, 2018) (Figure 4C).…”

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

“…Intracellular pathogens such as viruses stimulate the immune response by activating endosomal and cytoplasmic PRRs. The host cells are exposed to the viral dsRNA (double-strand RNA; a normal intermediate of RNA replication) during viral replication and are identified by RIG-I, endosomal-localized TLR3, MDA-5 (melanoma differentiation-associated protein 5), and interferon-induced sensors such as PKR [ 73 ], as shown in Figure 4 .…”