This article is part of the Top 10 Unanswered Questions in MPMI invited review series. Plants recognize the presence or invasion of microbes through cell surface-localized pattern recognition receptors (PRRs) and intracellular nucleotide-binding domain leucine-rich repeat receptors (NLRs). Although PRRs and NLRs are activated by ligands located in different subcellular compartments through distinct mechanisms, signals initiated from PRRs and NLRs converge into several common signaling pathways with different dynamics. Increasing evidence suggests that PRR- and NLR-mediated signaling extensively crosstalk and such interaction can greatly influence immune response outcomes. Sophisticated experimental setups enabled dissection of the signaling events downstream of PRRs and NLRs with fine temporal and spatial resolution; however, the molecular links underlying the observed interactions in PRR and NLR signaling remain to be elucidated. In this review, we summarize the latest knowledge about activation and signaling mediated by PRRs and NLRs, deconvolute the intimate association between PRR- and NLR-mediated signaling, and propose hypotheses to guide further research on key topics. [ ] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

Two members of the eight-member CALMODULIN-BINDING PROTEIN60 (CBP60) gene family, CBP60g and SYSTEMIC ACQUIRED RESISTANCE DEFICIENT1 (SARD1), encode positive regulators of plant immunity that promote the production of salicylic acid (SA) and affect the expression of SA-dependent and SA-independent defense genes. Here, we investigated the other six family members in Arabidopsis (Arabidopsis thaliana). Only cbp60a mutations affected growth of the bacterial pathogen Pseudomonas syringae pv maculicola ES4326. In contrast to cbp60g and sard1 mutations, cbp60a mutations reduced pathogen growth, indicating that CBP60a is a negative regulator of immunity. Bacterial growth was increased by cbp60g only in the presence of CBP60a, while the increase in growth due to sard1 was independent of CBP60a, suggesting that the primary function of CBP60g may be to counter the repressive effect of CBP60a. In the absence of pathogen, levels of SA as well as of several SA-dependent and SA-independent pathogen-inducible genes were higher in cbp60a plants than in the wild type, suggesting that the enhanced resistance of cbp60a plants may result from the activation of immune responses prior to pathogen attack. CBP60a bound calmodulin, and the calmodulin-binding domain was defined at the C-terminal end of the protein. Transgenes encoding mutant versions of CBP60a lacking the ability to bind calmodulin failed to complement null cbp60a mutations, indicating that calmodulin-binding ability is required for the immunity-repressing function of CBP60a. Regulation at the CBP60 node involves negative regulation by CBP60a as well as positive regulation by CBP60g and SARD1, providing multiple levels of control over the activation of immune responses.

Since signaling machineries for two modes of plant‐induced immunity, pattern‐triggered immunity (PTI) and effector‐triggered immunity (ETI), extensively overlap, PTI and ETI signaling likely interact. In an Arabidopsis quadruple mutant, in which four major sectors of the signaling network, jasmonate, ethylene, PAD4, and salicylate, are disabled, the hypersensitive response (HR) typical of ETI is abolished when the Pseudomonas syringae effector AvrRpt2 is bacterially delivered but is intact when AvrRpt2 is directly expressed in planta. These observations led us to discovery of a network‐buffered signaling mechanism that mediates HR signaling and is strongly inhibited by PTI signaling. We named this mechanism the ETI‐Mediating and PTI‐Inhibited Sector (EMPIS). The signaling kinetics of EMPIS explain apparently different plant genetic requirements for ETI triggered by different effectors without postulating different signaling machineries. The properties of EMPIS suggest that information about efficacy of the early immune response is fed back to the immune signaling network, modulating its activity and limiting the fitness cost of unnecessary immune responses. Synopsis A systems‐based analysis reveals crosstalk between pattern‐ and effector‐triggered plant immunity that enables modification of immune responses based on efficacy of early immune responses. The plant immune signaling network contains a signaling sector that mediates effector‐triggered immunity (ETI) and is inhibited by pattern‐triggered immunity (PTI). This signaling mechanism is named ETI‐mediating and PTI‐inhibited sector, or EMPIS. EMPIS mediates ETI in a compensatory manner with other signaling sectors. Differences in the timing of ETI and PTI signals reaching EMPIS determine qualitative differences in EMPIS requirements for ETI response triggered by different pathogen effectors.

Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2 ⁺ macrophages in various disease conditions, and substantial induction of TREM2 ⁺ NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2 ⁺ macrophages in disease pathogenesis.