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.

FIGURE 1

Integrins and complement—core structures, components, and functions. (a) Top: schematic of the general structure of integrin pairs with defining domains and the most common intracellular signalling scaffold engaged upon activation depicted. Bottom: overview of the 24 heterodimers formed by integrins in humans with their main ligands and biological functions. Boxes underlaid in light red mark the I domain‐containing α chains. (b) Top: simplified schematic of the three complement activation pathways and canonical complement system functions. Bottom: overview of the main proteins constituting the classic complement system cascade, categorized into five families: recognition molecules, proteases, TEP proteins of the terminal lytic pathway, and regulators/receptors

FIGURE 2

Evolution of integrins and complement. Upper part: simplified phylogenic tree of species with the evolutionary timeline of appearance in MYA aligned below. Bottom part: emergence of integrin and complement components during evolution. The appearance of key innate and adaptive immune system components and significant “leaps” in tissue development towards body cavities, the vascular system, and the liver are also shown. Timeline based on PMID: 27918074, 28405393, and 16598240

FIGURE 3

LFA‐1‐induced C3 licensing drives metabolic reprogramming in activated T‐cells. (a) Resting human CD4⁺ and CD8⁺ T‐cells sustain basal levels of C3 gene expression and generate continuously C3a and C3b via CTSL cleavage. Cell‐autonomous C3a stimulates the lysosomal C3aR that in turn sustains tonic mTORC1 activation needed for homeostatic survival. Diapedesis or the cognate APC/T‐cell interaction engages T‐cell expressed LFA‐1 (via ICAM‐1) and induces increased C3 gene expression and protein generation—C3 licensing. Timely incoming TCR signals are required to mediate increased intrinsic C3 activation (TCR signals also further activate LFA‐1), rapid surface translocation of C3a and the C3aR (denoted by an asterisk) and of C3b that then induces autocrine CD46 stimulation. CD46 downstream signals include the cleavage and nuclear translocation of its intracellular CYT‐1 domain that drives expression of nutrient transporters GLUT1 (glucose), LAT1 (amino acids, AA), fatty acid synthase or fatty acid synthesis (FAS), and the lysosomal scaffolder LAMTOR5. Together, these events support mTORC1 assembly at the lysosomes and high glycolysis, fatty acid synthesis, OXPHOS, and tricarboxylic acid cycle. CD46 also induces activation of intracellular C5 with C5a engaging the intracellular C5aR1 to produce ROS, NLRP3 inflammasome activation, and intrinsic active IL‐1β that sustains Th1 responses. Surface C5aR2 is a negative regulator of Th1 induction. The CD46/IL‐2R‐driven signals that co‐induce IL‐10 and Th1 contraction are not depicted here. Transmigration‐induced expression of a cell‐autonomous complosome is a defining feature of immune cells in tissue and also needed for normal monocyte/macrophage tissue activity (not shown). (b) Cell metabolic events known to be engaged by different integrins in a range of cells and their outcome on cell survival, proliferation, and migration (see text for details)

FIGURE 4

The integrin–complosome–metabolism network in the regulation of T‐cell effector function. Summary model depiction of the known cooperative actions of LFA‐1/integrins, the complosome, and key metabolic events that underly successful effector function induction in human CD4⁺ and CD8⁺ T‐cells. T‐cell receptor, growth factor receptor, and intrinsic inflammasome signals as well as negative/positive feedback loops (e.g., between generated metabolites and LFA‐1) have been omitted for simplicity