Integrin αDβ2 (CD11d/CD18) mediates experimental malaria-associated acute respiratory distress syndrome (MA-ARDS)

Abstract

BackgroundMalaria-associated acute respiratory distress syndrome (MA-ARDS) is a potentially lethal complication of clinical malaria. Acute lung injury in MA-ARDS shares features with ARDS triggered by other causes, including alveolar inflammation and increased alveolar-capillary permeability, leading to leak of protein-rich pulmonary oedema fluid. Mechanisms and physiologic alterations in MA-ARDS can be examined in murine models of this syndrome. Integrin αDβ2 is a member of the leukocyte, or β2 (CD18), sub-family of integrins, and emerging observations indicate that it has important activities in leukocyte adhesion, accumulation and signalling. The goal was to perform analysis of the lungs of mice wild type C57Bl/6 (aD+/+) and Knockout C57Bl/6 (aD−/−) with malaria-associated acute lung injury to better determine the relevancy of the murine models and investigate the mechanism of disease.MethodsC57BL/6 wild type (aD+/+) and deficient for CD11d sub-unit (aD−/−) mice were monitored after infection with 105Plasmodium berghei ANKA. CD11d subunit expression RNA was measured by real-time polymerase chain reaction, vascular barrier integrity by Evans blue dye (EBD) exclusion and cytokines by ELISA. Protein and leukocytes were measured in bronchoalveolar lavage fluid (BALF) samples. Tissue cellularity was measured by the point-counting technique, F4/80 and VCAM-1 expression by immunohistochemistry. Respiratory function was analysed by non-invasive BUXCO and mechanical ventilation.ResultsAlveolar inflammation, vascular and interstitial accumulation of monocytes and macrophages, and disrupted alveolar-capillary barrier function with exudation of protein-rich pulmonary oedema fluid were present in P. berghei-infected wild type mice and were improved in αDβ2-deficient animals. Key pro-inflammatory cytokines were also decreased in lung tissue from αD−/− mice, providing a mechanistic explanation for reduced alveolar-capillary inflammation and leak.ConclusionsThe results indicate that αDβ2 is an important inflammatory effector molecule in P. berghei-induced MA-ARDS, and that leukocyte integrins regulate critical inflammatory and pathophysiologic events in this model of complicated malaria. Genetic deletion of integrin subunit αD in mice, leading to deficiency of integrin αDβ2, alters lung inflammation and acute lung injury in a mouse model of MA-ARDS caused by P. berghei.

The Upregulation of Integrin αDβ2 (CD11d/CD18) on Inflammatory Macrophages Promotes Macrophage Retention in Vascular Lesions and Development of Atherosclerosis

“…Notably, the increased transcript for CD11d was previously detected in white adipose tissue during severe obesity (13) and in the lung during malaria-associated acute respiratory distress syndrome (9). Interestingly, both phenotypes are characterized by increased macrophage accumulation at the inflammatory site (50,51).…”

“…Recent studies demonstrate the increased interest in the potential contribution of CD11d to the immune response. It has been shown that anti-CD11d antibody reduced the inflammation (5–7) and macrophage accumulation (42,43) after spinal cord injury and CD11d-deficiency has a protective effect during P. berghei malaria infection (9). In contrast, the survival of CD11d −/− mice after Salmonella typhimurium sepsis was reduced (8).…”

“…Surprisingly, in comparison to other β 2 integrins, there is limited information on the function of CD11d/CD18. There are only a few publications that demonstrate the effect of CD11d on the development of the inflammatory response, and these have been studied in models of spinal cord injury (5–7), lethal systemic infections (8) and malaria (9). However, the molecular mechanism of CD11d function is still not understood.…”

Physiopathology of Malaria-Associated Acute Respiratory Distress Syndrome

“…The mechanisms of MA-ARDS are still not well established, research demonstrates the importance of CD8 + T cells in murine MA-ARDS, and the action of leukocytes integrins on pathogenesis [24,25]. However, there are two main strands that seek to clarify this pathogenesis.…”

“…This adhesion allows the parasite complete its life cycle without being eliminated by hemocathesis, thus increasing the severity of disease [5]. However, in MA-ARDS it is not very clear which adhesion molecule is responsible for the interaction of iRBC with pulmonary vascular endothelium [11,24,31].…”