Toll-like receptors and integrins crosstalk

Abstract

Immune system recognizes invading microbes at both pathogen and antigen levels. Toll-like receptors (TLRs) play a key role in the first-line defense against pathogens. Major functions of TLRs include cytokine and chemokine production. TLRs share common downstream signaling pathways with other receptors. The crosstalk revolving around TLRs is rather significant and complex, underscoring the intricate nature of immune system. The profiles of produced cytokines and chemokines via TLRs can be affected by other receptors. Integrins are critical heterodimeric adhesion molecules expressed on many different cells. There are studies describing synergetic or inhibitory interplay between TLRs and integrins. Thus, we reviewed the crosstalk between TLRs and integrins. Understanding the nature of the crosstalk could allow us to modulate TLR functions via integrins.

Keywords: crosstalk; toll-like receptor; αV integrin; β1 integrin; β2 integrin.

Figure 1

TLR signaling pathway TLR1, TLR2, TLR4, TLR5 and TLR6 are expressed on the cell surface. TLR3, TLR7, TLR8 and TLR9 are expressed in the endosome. Following ligand engagement, TLRs are dimerized, and interact either with MyD88 or TRIF. MyD88 signaling pathways involve NFκB and AP-1, both of which induces pro-inflammatory cytokines. Via TRIF, IRF3 and NFκB induces interferons and pro-inflammatory cytokines, respectively.

Figure 2

Integrin signaling Inside-out signal: Integrins are in an inactive conformation at baseline. However, the activation of receptors such as GPCRs, chemokine receptors, and TCR induces a cascade of events within the cells. The example shown here is via TCR. At the end, talin along with kindlin bind to β subunit of integrins, inducing its conformational change, which triggers the structural change of α subunit, allowing the integrin to bind to its ligand. Outside-in signal: Integrins that bind to their ligands cause cytoskeletal changes via focal adhesion molecules including focal adhesion kinase (FAK), leading to cell proliferation, survival, differentiation, and migration.

Figure 3

αMβ2 and TLR4 crosstalk The crosstalk between αMβ2 and TLR4 is shown.Inside-out signal: LPS binding to TLR4 induces the activation of many molecules including PI3K. PI3K facilitates the activation of αMβ2 intracellular adaptor proteins, therefore αMβ2 itself. Outside-in signal: Activated αMβ2 communicates with Src/Syk, which facilitates the degradation of MyD88 and TRIF. This will attenuate TLR4 activation signal. Of note, Syk is typically associated with other receptors like C-type lectin receptors (CLRs).