Targeting Integrins in Immunity: Precision Matters for Therapeutic Interventions

Integrins are transmembrane receptors that mediate interactions between the extracellular matrix (ECM) and cells. Integrins are expressed as heterodimers composed of an α-subunit and a β-subunit. Based on several α-subunits and β-subunits present in mammals, each integrin receptor is functionally distinct with specific ligand-binding and signalling features. Upon activation, integrins regulate diverse cellular functions via the formation of multi-protein assemblies with intracellular signalling proteins at the cell surface. However, integrin dysfunction or aberrant activation is also associated with various pathophysiological consequences. Driven by extensive pre-clinical studies demonstrating integrins as potential therapeutic targets, many drug discovery strategies have already been attempted over the decades with limited success. Molecular complexity and functional redundancy of integrin subunits, along with the toxicity associated with global targeting, remain major hurdles for therapeutic applications, emphasising the need for further understanding of integrin biology. Emerging evidence supports an integrated role of integrins in both innate and adaptive immune systems. Integrins are involved in a diverse array of immunological functions, including leukocyte recruitment, pro-inflammatory signalling, macrophage polarisation, hematopoietic stem cell (HSC) homing, immune homeostasis, Toll-like receptor (TLR) signalling, beta-cell development and function, and immune checkpoint regulation. It has therefore become more apparent why dysregulation of these integrin-mediated functions is often linked to various diseases. Integrin signalling is driven by several crucial downstream kinases, including focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), proto-oncogene tyrosine-protein kinase Src (SRC), and integrin-linked kinase (ILK). Encouraging pre-clinical and clinical studies have demonstrated the translational prospects of targeting integrins indirectly via these downstream molecules. Considering the adverse side effects often resulting from the global targeting of integrins, precise targeting of integrin functions via an indirect or cell-type-specific approach may represent a promising direction for future therapeutic development.