InVivoMAb anti-mouse IL-1α

InVivoMAb anti-mouse IL-1α (CLONE: ALF-161)

Hernández-Santos, N., et al (2018). "Lung Epithelial Cells Coordinate Innate Lymphocytes and Immunity against Pulmonary Fungal Infection" Cell Host Microbe 23(4): 511-522.e515. PubMed

Lung epithelial cells (LECs) are strategically positioned in the airway mucosa to provide barrier defense. LECs also express pattern recognition receptors and a myriad of immune genes, but their role in immunity is often concealed by the activities of “professional” immune cells, particularly in the context of fungal infection. Here, we demonstrate that NF-κB signaling in LECs is essential for immunity against the pulmonary fungal pathogen Blastomyces dermatitidis. LECs orchestrate innate antifungal immunity by augmenting the numbers of interleukin-17A (IL-17A)- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing innate lymphocytes, specifically “natural” Th17 (nTh17) cells. Innate lymphocyte-derived IL-17A and GM-CSF in turn enable phagocyte-driven fungal killing. LECs regulate the numbers of nTh17 cells via the production of chemokines such as CCL20, a process dependent on IL-1α-IL-1 receptor (IL-1R) signaling on LECs. Therefore, LECs orchestrate IL-17A- and GM-CSF-mediated immunity in an IL-1R-dependent manner and represent an essential component of innate immunity to pulmonary fungal pathogens.

Altmeier, S., et al (2016). "IL-1 Coordinates the Neutrophil Response to C. albicans in the Oral Mucosa" PLoS Pathog 12(9): e1005882. PubMed

Mucosal infections with Candida albicans belong to the most frequent forms of fungal diseases. Host protection is conferred by cellular immunity; however, the induction of antifungal immunity is not well understood. Using a mouse model of oropharyngeal candidiasis (OPC) we show that interleukin-1 receptor (IL-1R) signaling is critical for fungal control at the onset of infection through its impact on neutrophils at two levels. We demonstrate that both the recruitment of circulating neutrophils to the site of infection and the mobilization of newly generated neutrophils from the bone marrow depended on IL-1R. Consistently, IL-1R-deficient mice displayed impaired chemokine production at the site of infection and defective secretion of granulocyte colony-stimulating factor (G-CSF) in the circulation in response to C. albicans. Strikingly, endothelial cells were identified as the primary cellular source of G-CSF during OPC, which responded to IL-1α that was released from keratinocytes in the infected tissue. The IL-1-dependent crosstalk between two different cellular subsets of the nonhematopoietic compartment was confirmed in vitro using a novel murine tongue-derived keratinocyte cell line and an established endothelial cell line. These data establish a new link between IL-1 and granulopoiesis in the context of fungal infection. Together, we identified two complementary mechanisms coordinating the neutrophil response in the oral mucosa, which is critical for preventing fungal growth and dissemination, and thus protects the host from disease.

Copenhaver, A. M., et al (2015). "IL-1R signaling enables bystander cells to overcome bacterial blockade of host protein synthesis" Proc Natl Acad Sci U S A 112(24): 7557-7562. PubMed

The innate immune system is critical for host defense against microbial pathogens, yet many pathogens express virulence factors that impair immune function. Here, we used the bacterial pathogen Legionella pneumophila to understand how the immune system successfully overcomes pathogen subversion mechanisms. L. pneumophila replicates within macrophages by using a type IV secretion system to translocate bacterial effectors into the host cell cytosol. As a consequence of effector delivery, host protein synthesis is blocked at several steps, including translation initiation and elongation. Despite this translation block, infected cells robustly produce proinflammatory cytokines, but the basis for this is poorly understood. By using a reporter system that specifically discriminates between infected and uninfected cells within a population, we demonstrate here that infected macrophages produced IL-1alpha and IL-1beta, but were poor producers of IL-6, TNF, and IL-12, which are critical mediators of host protection. Uninfected bystander cells robustly produced IL-6, TNF, and IL-12, and this bystander response required IL-1 receptor (IL-1R) signaling during early pulmonary infection. Our data demonstrate functional heterogeneity in production of critical protective cytokines and suggest that collaboration between infected and uninfected cells enables the immune system to bypass pathogen-mediated translation inhibition to generate an effective immune response.

Hernandez, P. P., et al (2015). "Interferon-lambda and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection" Nat Immunol 16(7): 698-707. PubMed

The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon-lambda (IFN-lambda), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-lambda, both of which were ‘preferentially’ expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons.

Rogers, H. W., et al (1992). "Interleukin 1 participates in the development of anti-Listeria responses in normal and SCID mice" Proc Natl Acad Sci U S A 89(3): 1011-1015. PubMed

Using T- and B-cell deficient C.B-17 mice with the scid mutation, we have previously documented the existence of a T-cell-independent but interferon gamma-dependent pathway of macrophage activation that confers upon the host partial resistance to the facultative intracellular bacterium Listeria monocytogenes. This pathway is operative in both normal and SCID mice and consists of at least four components: interferon gamma, tumor necrosis factor, macrophages, and natural killer cells. Here we demonstrate that interleukin 1 also participates in this pathway but at a different site of action. Using monoclonal antibodies that neutralize the biologic activities of interleukin 1 alpha and interleukin 1 beta, we document that interleukin 1 participates neither directly in the induction of interferon gamma from isolated SCID natural killer cells nor in the antigen-specific activation of CD4+ T cells derived from Listeria-immune C.B-17 mice. In contrast, injection of a mixture of anti-interleukin 1 alpha, anti-interleukin 1 beta, and a newly derived monoclonal antibody specific for the murine type I interleukin-1 receptor into either SCID or normal C.B-17 mice blocked the in vivo elaboration of class II major histocompatibility complex-positive macrophages after infection of the animals with Listeria. Moreover, SCID mice treated with the anti-interleukin-1 mixture failed to control the growth of Listeria in vivo and eventually succumbed to the infection. These results document that endogenously produced interleukin 1 plays an obligate role in the Listeria-dependent induction of activated macrophages in vivo and demonstrate that the action of interleukin 1 is distinct from the generation of natural killer cell-derived interferon gamma.