Graphical AbstractHighlights d Activated immunity engages in an energetic trade-off with homeothermy d Immunity reprograms hepatic metabolism to meet host energetic priorities d Energetic trade-off between immunity and homeothermy promotes disease tolerance d Hypometabolic states promote disease tolerance during bacterial infections In BriefImmune activation after infection is metabolically costly, competing for energy with the maintenance of normal body temperature, and this dynamic trade-off leads to preferential use of tolerance as a mechanism of bacterial defense. SUMMARYHost defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance.

SUMMARY For placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known. Here, we provide evidence that the ‘alarmin’ IL-33, a nuclear cytokine that activates type 2 immune responses, licenses brown and beige adipocytes for uncoupled respiration. We find that, in absence of IL-33 or ST2, beige and brown adipocytes develop normally but fail to express an appropriately spliced form of Ucp1 mRNA, resulting in absence of UCP1 protein, and impairment in uncoupled respiration and thermoregulation. Together, these data suggest that IL-33 and ST2 function as a developmental switch to license thermogenesis during the perinatal period.

The amount of an Ag used for stimulation affects the type and magnitude of T cell responses. In this study we have investigated the primary response of naive CD4+ T cells derived from OVA-specific TCR-transgenic mice (OVA23-3) upon stimulation with varying doses of the antigenic peptide, OVA323–339. IL-4 expression was maximal with 50 nM Ag and decreased significantly with increasing doses. In contrast, IFN-γ expression, which was also detected at 50 nM Ag, increased with increasing doses. The expression patterns of mRNA for the Th2-specific transcription factors GATA-3 and c-Maf were parallel to that of IL-4. These expression profiles were not altered by the addition of anti-IL-4 plus anti-IL-12 mAbs, suggesting that cytokine receptor signaling is not essential. Naive CD4+ T cells stimulated with 5 nM Ag elicited IgM secretion from cocultured B cells, whereas those stimulated with 50 nM Ag or more elicited apoptosis of B cells. This may be because at lower doses of Ag (5 nM), naive CD4+ T cells express CD40 ligand and OX40, whereas at higher doses (50 nM), they express Fas ligand. Clearly, the expression of each type of molecule depends on the Ag dose, and different molecules had different expression patterns. Thus, in the primary response, naive CD4+ T cells can exhibit different functions depending on the dose of Ag.

Our paper reported perinatal licensing of thermogenesis by IL-33 signaling. During the preparation of Figure S1A, we inadvertently duplicated the representative section of inguinal white adipose tissue (iWAT) from wild-type at day postnatal day 35 (P35) and inserted the duplicate as the representative image of IL33 −/− animals at postnatal day 7 (P7). We have now corrected the online version of our paper, providing a revised version of Figure S1 showing the correct image of IL33 −/− P7 iWAT tissue. This error does not affect the results in the paper or the interpretation of the data. We apologize for any confusion this error may have caused.

Summary It has been reported that the stimulation of neutrophils with N‐formyl‐Met‐Leu‐Phe (fMLF), an agonist for formyl peptide receptor (Fpr) 1, renders cells unresponsive to other chemoattractants in vitro. This is known as cross‐desensitization, but its functional relevance in neutrophil migration in vivo has not been investigated. Here, we show that precedent stimulation of mouse neutrophils with compound 43, a non‐peptidyl agonist for mouse Fpr1 and Fpr2, rendered the cells unresponsive to a second stimulation with C5a, leukotriene B4, or keratinocyte‐derived cytokine (KC) in calcium mobilization and chemotaxis assays in vitro. The expression of chemokine (C‐X‐C motif) receptor 2 (CXCR2) on the surface of neutrophils was concomitantly diminished by stimulating the cells with the compound. Moreover, oral administration of the compound to mice before they were exposed to lipopolysaccharide (LPS) aerosol resulted in a dose‐dependent reduction in the neutrophil count in bronchoalveolar lavage fluid. The expression of CXCR2 on blood neutrophils was also reduced in the compound‐administered mice. The recipient mice that underwent adoptive transfer of fluorescence‐labelled neutrophils that had been incubated with the compound showed a substantial decrease in neutrophil counts in bronchoalveolar lavage fluid after they were exposed to LPS, when compared with the control mice to which vehicle‐treated neutrophils had been transferred. These results are consistent with the idea that the agonist for Fpr1 and Fpr2 induced cross‐desensitization in neutrophils and attenuated neutrophil migration into the airways. Our results also revealed the unpredicted effect of an Fpr1 and Fpr2 dual agonist, which may act as a functional antagonist for multiple chemoattractant receptors in vivo.

Abstract. A pyrazolone compound acting as a formyl peptide receptor (FPR) 2/ALX-selective agonist has been reported, but its pharmacological activities on human FPRs (hFPRs) and mouse FPRs (mFprs) have not been well demonstrated. In this study, we found that this compound, designated as compound A, induced concentration-dependent calcium flux not only in Chinese hamster ovary (CHO) cells expressing hFPR2/ALX but also in cells expressing hFPR1, mFpr1, or mFpr2. It also induced the receptor internalization of hFPR1 and hFPR2/ ALX and, accordingly, induced calcium influx and chemotactic responses in both human and mouse neutrophils. Our study revealed that compound A is in fact an FPR1 and FPR2/ALX dual agonist.

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