Landon K. Oetjen

New insights into basophil heterogeneity.

Basophils have become increasingly recognized as important innate immune cells that mediate antihelminth immunity and barrier inflammation. Recent discoveries have uncovered previously unrecognized heterogeneity in basophil populations. However, how diversity in basophil regulation and function impacts human disease remains poorly defined. The goal of the present review is to highlight how new insights into basophil heterogeneity can help us to better understand disease pathogenesis and inform the development of new therapeutics.

Sensory TRP channels contribute differentially to skin inflammation and persistent itch

Although both persistent itch and inflammation are commonly associated with allergic contact dermatitis (ACD), it is not known if they are mediated by shared or distinct signaling pathways. Here we show that both TRPA1 and TRPV1 channels are required for generating spontaneous scratching in a mouse model of ACD induced by squaric acid dibutylester (SADBE), a small molecule hapten, through directly promoting the excitability of pruriceptors. TRPV1 but not TRPA1 channels protect the skin inflammation, as genetic ablation of TRPV1 function or pharmacological ablation of TRPV1-positive sensory nerves promotes cutaneous inflammation in the SADBE-induced ACD. Our results demonstrate that persistent itch and inflammation are mediated by distinct cellular and molecular mechanisms in a mouse model of ACD. Identification of distinct roles of TRPA1 and TRPV1 in regulating itch and inflammation may provide new insights into the pathophysiology and treatment of chronic itch and inflammation in ACD patients.Allergic contact dermatitis is associated both with persistent itch and inflammation, but it is not known if these are mediated by shared signaling pathways. The authors show that persistent itch requires both TRPA1 and TRPV1, while TRPV1 has a protective role against skin inflammation in mice.

MicroRNA signature of central nervous system-infiltrating dendritic cells in an animal model of multiple sclerosis

Innate immune cells are integral to the pathogenesis of several diseases of the central nervous system (CNS), including multiple sclerosis (MS). Dendritic cells (DCs) are potent CD11c+ antigen‐presenting cells that are critical regulators of adaptive immune responses, particularly in autoimmune diseases such as MS. The regulation of DC function in both the periphery and CNS compartment has not been fully elucidated. One limitation to studying the role of CD11c+ DCs in the CNS is that microglia can upregulate CD11c during inflammation, making it challenging to distinguish bone marrow‐derived DCs (BMDCs) from microglia. Selective expression of microRNAs (miRNAs) has been shown to distinguish populations of innate cells and regulate their function within the CNS during neuro‐inflammation. Using the experimental autoimmune encephalomyelitis (EAE) murine model of MS, we characterized the expression of miRNAs in CD11c+ cells using a non‐biased murine array. Several miRNAs, including miR‐31, were enriched in CD11c+ cells within the CNS during EAE, but not LysM+ microglia. Moreover, to distinguish CD11c+ DCs from microglia that upregulate CD11c, we generated bone marrow chimeras and found that miR‐31 expression was specific to BMDCs. Interestingly, miR‐31‐binding sites were enriched in mRNAs downregulated in BMDCs that migrated into the CNS, and a subset was confirmed to be regulated by miR‐31. Finally, miR‐31 was elevated in DCs migrating through an in vitro blood–brain barrier. Our findings suggest miRNAs, including miR‐31, may regulate entry of DCs into the CNS during EAE, and could potentially represent therapeutic targets for CNS autoimmune diseases such as MS.

TRPV4 Channel Signaling in Macrophages Promotes Gastrointestinal Motility via Direct Effects on Smooth Muscle Cells

Summary Intestinal macrophages are critical for gastrointestinal (GI) homeostasis, but our understanding of their role in regulating intestinal motility is incomplete. Here, we report that CX3C chemokine receptor 1‐expressing muscularis macrophages (MMs) were required to maintain normal GI motility. MMs expressed the transient receptor potential vanilloid 4 (TRPV4) channel, which senses thermal, mechanical, and chemical cues. Selective pharmacologic inhibition of TRPV4 or conditional deletion of TRPV4 from macrophages decreased intestinal motility and was sufficient to reverse the GI hypermotility that is associated with chemotherapy treatment. Mechanistically, stimulation of MMs via TRPV4 promoted the release of prostaglandin E2 and elicited colon contraction in a paracrine manner via prostaglandin E receptor signaling in intestinal smooth muscle cells without input from the enteric nervous system. Collectively, our data identify TRPV4‐expressing MMs as an essential component required for maintaining normal GI motility and provide potential drug targets for GI motility disorders. Graphical Abstract Figure. No caption available. HighlightsMacrophage‐specific Trpv4‐deficient mice display reduced gastrointestinal motilityDirect interactions between MMs and smooth muscle cells produce colon contractionEnteric nervous system is not involved in macrophage‐mediated colon contractionTRPV4 inhibition reverses GI hypermotility associated with chemotherapy treatment &NA; How intestinal macrophages regulate intestinal motility remains poorly understood. Luo et al. demonstrate that muscularis macrophages expressing the TRPV4 channel promote GI motility by directly affecting the function of intestinal smooth muscle cells independent of the enteric nervous system.

Interactions of the immune and sensory nervous systems in atopy

A striking feature underlying all atopic disorders, such as asthma, atopic dermatitis, and food allergy, is the presence of pathologic sensory responses, reflexes, and behaviors. These symptoms, exemplified by chronic airway irritation and cough, chronic itch and scratching, as well as gastrointestinal discomfort and dysfunction, are often cited as the most debilitating aspects of atopic disorders. Emerging studies have highlighted how the immune system shapes the scope and intensity of sensory responses by directly modulating the sensory nervous system. Additionally, factors produced by neurons have demonstrated novel functions in propagating atopic inflammation at barrier surfaces. In this review, we highlight new studies that have changed our understanding of atopy through advances in characterizing the reciprocal interactions between the immune and sensory nervous systems.