The chemokine system in innate immunity

Abstract

Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system. Chemokines control the release of innate immune cells from the bone marrow during homeostasis as well as in response to infection and inflammation. They also recruit innate immune effectors out of the circulation and into the tissue where, in collaboration with other chemoattractants, they guide these cells to the very sites of tissue injury. Chemokine function is also critical for the positioning of innate immune sentinels in peripheral tissue and then, following innate immune activation, guiding these activated cells to the draining lymph node to initiate and imprint an adaptive immune response. In this review, we will highlight recent advances in understanding how chemokine function regulates the movement and positioning of innate immune cells at homeostasis and in response to acute inflammation, and then we will review how chemokine-mediated innate immune cell trafficking plays an essential role in linking the innate and adaptive immune responses.

Figure 1.

Chemokine control of innate immune cell migration in homeostasis and inflammation. Under homeostatic conditions, CX3CR1⁺ monocytes presumably migrate into the periphery following CX3CL1 gradients, mast cell precursors migrate into the gastrointestinal tract following CXCL1 and CXCL2 gradients, and eosinophils migrate into tissue following CCL11 gradients. In acute inflammation, neutrophils may leave the bloodstream and migrate into the periphery following gradients of LTB₄, CXCL1, CXCL2, CXCL8, CCL3, and CCL5. CCR2⁺ monocytes will migrate following CXCL1, CXCL2, CXCL8, and CCL2 gradients. Mast cell precursors also migrate in response to leukotriene B4 (LTB₄) and leukotrine D4 (LTD₄) via activation of their respective G-protein-coupled receptors BLT1 and CYSLT1. Eosinophils will migrate into inflammatory sites in response to CCL11, CCL24, and CCL26 gradients. NK cells will migrate following CXCL9, CXCL10, CCL3, CCL4, and CCL5 gradients.

Figure 2.

Mechanisms of neutrophil migration in the inflamed periphery. (A) Neutrophils migrate to sites of tissue damage by following sequential chemoattractant gradients. Neutrophils first follow CXCL2 gradients, and then, in areas of tissue necrosis, follow gradients of endogenous formyl peptides via FPR1 signaling. (B) Neutrophils can amplify their own recruitment through the production of chemokines. Neutrophils migrate to inflammatory sites by following LTB₄ gradients (1) where they are activated by inflammatory stimuli and produce additional chemokines, such as CXCL2 (2) that promote further neutrophil entry by establishing an additional chemokine gradient (3). (C) Neutrophils can be activated by chemotactic agents, such as formyl peptides or C5a, leading to LTB₄ production, which establishes a relay system for neutrophil swarming. Formyl-peptide or C5a-activated neutrophils (1) produce LTB₄ (2), which creates a chemoattactant gradient that induces more neutrophils to enter and swarm to the site of inflammation (3).