Lipid-cytokine-chemokine cascades orchestrate leukocyte recruitment in inflammation

Abstract

Chemoattractants are pivotal mediators of host defense, orchestrating the recruitment of immune cells into sites of infection and inflammation. Chemoattractants display vast chemical diversity and include bioactive lipids, proteolytic fragments of serum proteins, and chemokines (chemotactic cytokines). All chemoattractants induce chemotaxis by activating seven-transmembrane-spanning GPCRs expressed on immune cells, establishing the concept that all chemoattractants are related in function. However, although chemoattractants have overlapping functions in vitro, recent in vivo data have revealed that they function, in many cases, nonredundantly in vivo. The chemically diverse nature of chemoattractants contributes to the fine control of leukocyte trafficking in vivo, with sequential chemoattractant use guiding immune cell recruitment into inflammatory sites. Lipid mediators frequently function as initiators of leukocyte recruitment, attracting the first immune cells into tissues. These initial responding immune cells produce cytokines locally, which in turn, induce the local release of chemokines. Local chemokine production then markedly amplifies subsequent waves of leukocyte recruitment. These new discoveries establish a paradigm for leukocyte recruitment in inflammation--described as lipid-cytokine-chemokine cascades--as a driving force in the effector phase of immune responses.

Figure 1.. General principle of “lipid-cytokine-chemokine cascades” in the initiation of inflammatory responses.

Upon stimulation, the tissue sentinel leukocyte immediately begins to release LTB₄ and possibly additional lipid mediators. In turn, the first effector immune cells are recruited into the inflammatory site by lipid mediators. These first recruited immune cells release proinflammatory cytokines, which activate tissue resident cells. Activated tissue resident cells release chemokines, which amplify immune cell recruitment into the inflammatory site.

Figure 2.. Lipid-cytokine-chemokine cascades driving allergic asthma.

In allergic asthma, T_H2 cells and eosinophils are recruited into the airway lumen by a lipid-cytokine-chemokine cascade consisting of LTB₄-T_H2 cytokines-CCR3/CCR4 ligands. (Left panel) The cascade is initiated after exposure to allergen in the lung with the activation of mast cells by FcεRI crossing, inducing the release of LTB₄ and PGD₂, which recruit the first T_H2 cells into the lung interstitium by activating BLT1 and DP2 on T_H2 cells, respectively. Of note, DP2 expressed on human but not murine T_H2 cells. (Middle panel) Recruited T_H2 cells release their signature cytokines IL-4, IL-13, and IL-5. These cytokines activate resident lung cells, particularly mDCs, but also lung epithelial cells and endothelial cells. (Right panel) The aforementioned cells, in turn, release CCL17 and CCL22 (CCR4 ligands), as well as CCL11 and CCL24 (CCR3 ligands), which recruit T_H2 cells and eosinophils, respectively, into the lung. Thus, the recruitment of immune cells into the lung is vastly amplified, and allergic asthma is fully established.

Figure 3.. Lipid-cytokine-chemokine cascade drives inflammatory arthritis.

Inflammatory arthritis in the K/BxN murine model largely depends on the recruitment of neutrophils into the joint, which is driven by a cascade of chemoattractants, constituted by LTB₄-IL-1β-CCR1/CXCR2 ligands. (Left panel) Neutrophils pioneering in the joint space are activated, possibly by immune complexes, and release LTB₄, which recruits additional neutrophils into the joint by activating BLT1 on neutrophils. (Middle panel) BLT1^+/+ neutrophils are further activated within the joint and release IL-1β. Neutrophil-derived IL-1β activates resident cells in the joint, particularly synovial fibroblasts and endothelial cells, to induce the release of CCR1 and CXCR2 ligands from these cells. (Right panel) The recruitment of neutrophils into the joint is vastly amplified by chemokines. Thus, huge numbers of neutrophils are recruited into the joint—first, primarily through CCR1 ligands and later, through CXCR2 ligands. In addition to resident structural cells in the joint, neutrophils recruited into the joint contribute to the production of CCR1 and CXCR2 ligands, especially CXCL2, this way reinforcing their own recruitment.