Tissue-specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge
Hoyer FF, Naxerova K, Schloss MJ, et al. Immunity. 2019; 51(5):899–914.
Sepsis results in an aberrant systemic inflammatory state affecting the entire organism. Counterintuitively, local ischemic processes such as myocardial infarction (MI) and stroke also lead to systemic inflammation from an analogous overactive immune response. It is well known that macrophages residing in all major organs are among the first innate immune cell responders to local damages.1 However, how they respond to remote damages and subsequent systemic inflammation, and in changing their molecular profiles following such responses are not well understood. In the present study,2 Nahrendorf et al comprehensively profiled murine organ macrophage responses to systemic inflammation such as sepsis (induced by cecal ligation and puncture [CLP]), MI, or stroke. Employing a fate-mapping strategy, they observed that MI, stroke, and CLP induced an increase of macrophages residing in remote organs and that such an increase predominantly resulted from local proliferation of resident macrophages rather than recruitment of circulating macrophages. They further observed that in comparison to that of steady-state resident macrophages, the gene expression of these macrophages after remote ischemia or CLP was significantly altered in a tissue-specific manner. Such alterations in gene expression also carried functional consequences. Specifically, they found that alveolar macrophages were primed by MI to combat bacterial pneumonia via enhanced IFNγ-mediated bacterial clearance, whereas epidermal growth factor signaling in the same macrophages post-MI compromised hosts’ ability to survive bacterial pneumonia. Similarly, they observed that during sepsis by CLP, cardiac macrophages protected cardiomyocytes through an IL-10-dependent protein-protein interaction network.
The approach of using bulk RNA sequencing, flow cytometry, single-cell RNA sequencing, and calculated wet-lab experiments is one that effectively incorporates computational strategies into basic biological research, integrating and motivating biological experiments for greater confidence in discovering real factors that affect a specific process. Nahrendorf et al successfully demonstrated how this integrative approach could be effectively employed to gain mechanistic insights on organ-specific responses of tissue-resident macrophages in a variety of injury contexts. In addition, the current study raises several intriguing questions specific to organ transplantation: (1) When tissue-resident macrophages are transplanted along with a donor organ to a recipient, what would be their capacity to proliferate and respond to an injury that incorporates both ischemia-reperfusion and alloimmune insults? (2) What would be the impact of various immunosuppressive drugs on such responses of tissue-resident macrophages? (3) What would be the relative contributions of recipient migratory macrophages versus donor tissue-resident macrophages in shaping the host immune response, innate or adaptive, to the transplanted organ? Lastly, (4) In light of the recent description of “trained immunity,”3 namely, epigenetic reprogramming of macrophages in response to enhanced or muted inflammatory status, how would such “risk storage” imprinted in tissue macrophages be qualified and/or quantified for prognosticating the risk to injury in a “future” transplantation of such an organ? While the current study aimed to profile tissue-resident macrophages in inflammatory conditions that are not alloimmune-driven, it has provided a landmark “atlas” for future studies of such macrophages in the unique context of solid organ transplantation.
Missing Self Triggers NK Cell-mediated Chronic Vascular Rejection of Solid Organ Transplants
Koenig A, Chen C-C, Marçais A, et al. Nat Commun. 2019; 25(10):5350.
In solid organ transplantation, graft endothelium is the first biological interface between donor alloantigens and circulating host antibodies. It is thought that binding of circulating host anti-human leukocyte antigen (HLA) donor-specific antibodies (DSAs) to the alloantigen targets on graft endothelium either triggers the classical complement pathway or engages surface Fc receptors of innate immune effector cells to mediate direct damage to the endothelial cells (ECs). Therefore, the presence of microvascular inflammation (MVI) in graft biopsy is traditionally considered as a diagnostic hallmark of antibody-mediated rejection.1 This notion is now challenged by findings by Koenig et al in this study. Here,2 in studying 129 kidney allograft biopsies with classical MVI, they found that 41.1% of these recipients in fact did not have detectable circulating DSAs or non-HLA antibodies, such as antiangiotensin II type 1 receptor, anti-MHC class I polypeptide-related sequence, both previously implicated in the pathogenesis of MVI. However, the mere presence of MVI had an adverse effect on graft survival despite the absence of any antidonor humoral responses. In searching for a possible underlying cause of graft damage, the authors used a combination of clinical data and preclinical murine studies and observed that (1) natural killer (NK) cells prominently infiltrated kidney allografts in which MVI was clearly present but DSAs were absent or present but unable to fix complement; (2) genetic analysis of these donor-recipient pairs revealed a higher prevalence of mismatches between donor HLA class I and recipient inhibitory killer cell immunoglobulin-like receptors, predicting a higher prevalence of “missing self”; (3) the “missing self” signal was further amplified by ischemia/reperfusion injuries (IRI) or viral infections, 2 frequent scenarios encountered in clinical transplantation, activating recipient NK cells; this was shown both as clinical correlations as well as in in vitro EC-NK cocultures where the activated NK cells consistently damaged the cocultured allogeneic ECs; (4) heart allografts from mice with β2 microglobulin deficiency (therefore missing self HLA class I expression) transplanted to β2 microglobulin sufficient recipients suffered from worse MVI following NK cell priming by either mild IRI or Poly (I:C) (as a surrogate for viral infection); (5) lastly, NK cell activation induced by the missing self was dependent on the mammalian target of rapamycin (mTOR) pathway, specifically the mTORC1 pathway; consequently, recipient treatment with an mTOR inhibitor rapamycin, but not a calcineurin inhibitor, effectively prevented the missing self-induced NK-mediated MVI.
This thoughtful and well-conducted study has significant implications in both clinical practice and basic transplant immunobiology. While findings here should certainly be interpreted in the inevitable context of clinical confounding factors, they suggest important and previously unrecognized considerations in clinical practice of caring for transplant recipients with MVI. Specifically, MVI should be first categorized into those with antidonor humoral responses and those without. In MVI without antidonor humoral responses, the possibility of missing self-mediated NK cell-dependent pathogenesis should be closely investigated. In parallel, processes exacerbating NK cell activation such as IRI and viral infections should be minimized, and addition and/or conversion to an mTOR inhibitor-based immunosuppression regimen should be considered when clinically not contraindicated. At a more basic level, the current study also challenges the notion of adaptive immunity being the sole instigator of allograft rejection, and unveiled a role of missing self-induced NK cell activation in promoting transplant rejection, joining force with newly emerging data3 on the role of innate immunity in allorecognition.
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