Open Research Projects, Research

Mechanisms by which innate immune crosstalk maintains kidney homeostasis and protects from autoimmune organ damage

Principle Investigator

Scientific interest within the context of the graduate college:

Tissue resident immune cells maintain organ health by mechanisms that are not well understood. We propose to explore the mechanisms by which ILC crosstalk with resident macrophages to maintain homeostasis in the kidney.

Project description:

Introduction: Tissue resident immune cells are present in all organs at homeostasis, however their role in maintaining organ homeostasis vs. promoting disease remains poorly understood. We have recently interrogated the role of innate lymphoid cells expressing the activating receptor NKp46 in lupus nephritis, a prototypic autoimmune disease where autoantibodies and immune complex deposition initiate a chronic inflammatory response, which in some patients is mild, while in others severe. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blocking and genetic deficiency, we showed that tissue-resident NKp46+ ILC are crucial signal amplifiers of disease-associated kidney macrophage dynamics and epithelial cell injury. NKp46 signaling in a distinct subset of ILC1 instructed an unconventional immune-regulatory transcriptional program. NKp46activation instructed disease-associated macrophages to adopt pro-inflammatory programs that led to proximal tubular damage and periglomerular fibrosis. While these data revealed that NKp46 activation in ILC1 constitutes a previously unrecognized, critical tissue rheostat that regulates disease-associated macrophage dynamics and amplifies macrophage-mediated epithelial tissue damage in autoimmune hosts, the role of tissue resident ILC1 at homeostasis remains elusive, and yet, we have identified frequent physical association of ILC1 with tissue resident macrophages. Here, we hypothesize that resident ILC1 are critical for the differentiation and function of tissue resident macrophages in multiple organs. Promoting healthy interactions of resident ILC1 and macrophages may thus be a valid strategy to protect from autoimmune organ damage. To address this hypothesis, we propose the following specific aims:

Aim 1: To explore the role of the activating receptors, expressed by tissue resident ILC1, in regulating ILC1 phenotype and function in various organs, such as the kidney, small intestine and the dura mater.

Aim 2: To explore the role of ILC1 in instructing tissue resident macrophage function at homeostasis and in response to type I interferons, TLR7 ligands or immune complexes.

Aim 3: To identify mechanisms by which ILC1 are activated at homeostasis and in the presence of elevated type I interferons.


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