Integrins meet complement: The evolutionary tip of an iceberg orchestrating metabolism and immunity

Abstract

Immunologists have recently realized that there is more to the classic innate immune sensor systems than just mere protection against invading pathogens. It is becoming increasingly clear that such sensors, including the inflammasomes, toll‐like receptors, and the complement system, are heavily involved in the regulation of basic cell physiological processes and particularly those of metabolic nature. In fact, their “non‐canonical” activities make sense as no system directing immune cell activity can perform such task without the need for energy. Further, many of these ancient immune sensors appeared early and concurrently during evolution, particularly during the developmental leap from the single‐cell organisms to multicellularity, and therefore crosstalk heavily with each other. Here, we will review the current knowledge about the emerging cooperation between the major inter‐cell communicators, integrins, and the cell‐autonomous intracellularly and autocrine‐active complement, the complosome, during the regulation of single‐cell metabolism. Linked Articles This article is part of a themed issue on Canonical and non‐canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc

Complement C1s and C4d as Prognostic Biomarkers in Renal Cancer: Emergence of Noncanonical Functions of C1s

“…Therefore, intracellular C1s may get activated and exert enzymatic activity toward its canonical substrates but in a non-canonical location. Therefore, the activity of C1s may result in functions, similar to the ones described for C3 in T cells [55].…”

The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology

“…Additionally, the treasure chest of CR3-mediated interactions and functions is still not exhausted. For example, recent studies showed a link between the complement system and integrins (especially LFA-1) in orchestrating metabolism and immunity ( 1 ) through regulation of the intracellular complement system (i.e. the complosome) ( 336 ), which is required for Th1 responses.…”

“…They provide major molecular links between extracellular matrix components, adhesion molecules, and plasma proteins. As a phylogenetically ancient family of large glycoproteins with origins that can be traced back 750 million years, integrins coevolved with the development of specialized cells, tissue, and metabolic and host defense systems such as the complement system ( 1 ). Integrins transmit signals bidirectionally across the plasma membrane and participate in a wide range of processes, such as inflammation, tissue homeostasis, and angiogenesis.…”

Complement Has Brains—Do Intracellular Complement and Immunometabolism Cooperate in Tissue Homeostasis and Behavior?

“…LFA-1 expressed on immune cells is engaged by intercellular adhesion molecule 1 (ICAM-1) expressed on endothelial cells during diapedesis or cognate antigen presenting cell (APC)-T cells during priming. LFA-1-driven C3 gene transcription is, at least in part, dependent on the TF activation protein 1 (AP-1) ( 27 , 82 ). This ‘C3 licensing’ (which remains stable for about 12 h) increases intracellular stores of C3 in anticipation of antigen encounter in tissues.…”