Saturday, December 21, 2024 12/21/2024

Role of spleen educated monocytes in mediating ischemia-reperfusion injury followinglung transplant surgery

Award Number: R01HL147575
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Extremely high rates (>50%) of primary graft dysfunction (PGD) due to ischemia reperfusion injury (IRI) are the predominant cause of impaired post-lung transplant outcomes resulting in both short-term mortality as well as chronic lung allograft rejection. PGD is driven by the recruitment of neutrophils into the allograft which, upon extravasation into the alveolar space, undergo NETosis to cause irreversible lung injury. We and others have found that depleting neutrophils can ameliorate PGD but is not clinically feasible given their importance in pathogen clearance. Accordingly, in the prior funding period, we focused on understanding the mechanisms that drive neutrophil trafficking to the lung following transplantation. Our work facilitated the discovery of a fascinating multicellular signaling pathway that underlies PGD: A) donor-origin Ly6ClowCCR2- non-classical monocytes (NCM) retained in donor lungs release neutrophil chemokine CXCL12 to recruit recipient neutrophils, B) bone- marrow derived recipient Ly6ChighCCR2+ classical monocytes (CM) stored in the spleen are mobilized to the allograft through donor NCM-dependent activation of donor alveolar macrophages (AM), C) upon entry into the allograft, the CM permeabilize the pulmonary endothelium through IL-1β dependent downregulation of zona occludens-2 and tight junction protein Claudin-5 to enable extravasation of recipient neutrophils. Experiments performed in the prior cycle and additional preliminary data further suggested that the CM are activated through toll receptor signaling (TLR) and the release of IL-1β is NLRP3 inflammasome dependent. Excitingly, our data uncovers a novel function of the spleen in priming bone marrow derived CM to activate the NLRP3 inflammasome. Single cell transcriptomics and high resolution spatial intravital imaging indicated that the splenic metallophilic macrophages released TGF- to recruit CM to the spleen independent of CCR2-CCL2 axis while the red pulp macrophages primed them release IL-1β through the activation of NLRP3 inflammasome, a process that required 3 days. These data fundamentally change the understanding of the spleen from a monocyte reservoir into an active immune organ necessary for a coordinated response to injury. Collectively, our data strongly support the hypothesis that after lung transplantation, IL-1 released by spleen-primed CM recruited to the lung is dependent on TLR signaling and activation of NLRP3 inflammasome. We will test our hypothesis using two aims: Aim 1. Determine the mechanisms of activation of CM after migration from spleen to the transplanted lung. Aim 2. Determine if spleen functions as both a reservoir and site for monocyte priming to mediate lung allograft injury. Our experimental design takes advantage of our models of sequential spleen and lung transplantation as well as state-of-the-art techniques such as spatial intravital imaging and single cell/spatial transcriptomics. We will use complementary genetic and pharmacological techniques to perform causal experiments to prove our hypothesis while creating a rich molecular atlas of human ischemia reperfusion injury. These studies will facilitate the rapid translation of our findings to clinical practice.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $772,046 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	6	5/15/2024	NON-COMPETING CONTINUATION	$772,046
														Subtotal = $772,046

Issue Date FY: 2023 ( Subtotal = $797,403 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	5	7/6/2023	COMPETING CONTINUATION	$797,403
														Subtotal = $797,403

Issue Date FY: 2022 ( Subtotal = $591,457 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	4	3/9/2022	NON-COMPETING CONTINUATION	$532,310
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	001	4	6/14/2022	NON-COMPETING CONTINUATION	$59,147
														Subtotal = $591,457

Issue Date FY: 2021 ( Subtotal = $591,457 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	3	3/17/2021	NON-COMPETING CONTINUATION	$591,457
														Subtotal = $591,457

Issue Date FY: 2020 ( Subtotal = $591,457 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	2	3/24/2020	NON-COMPETING CONTINUATION	$591,457
														Subtotal = $591,457

Issue Date FY: 2019 ( Subtotal = $592,500 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	1	3/25/2019	NEW	$592,500
														Subtotal = $592,500

Grand Total All Awards = $3,936,320

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Role of spleen educated monocytes in mediating ischemia-reperfusion injury followinglung transplant surgery

Award Number: R01HL147575

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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