Methods for modulating inflammasome activity and inflammation in the lung

Abstract

The present invention provides compositions and methods for reducing inflammation in the lungs of a mammal that is afflicted by a condition that leads to inflammation in the lungs. The compositions and methods described herein include agents that inhibit inflammasome signaling in the mammal such as antibodies directed against inflammasome components used alone or in combination with extracellular vesicle uptake inhibitor(s).

What is claimed is: 
     
         1 . A method of treating inflammation in lungs of a patient in need thereof, the method comprising: administering to the patient a composition comprising an agent that inhibits inflammasome signaling, whereby the inflammation in the lungs of the patient is treated. 
     
     
         2 . The method of  claim 1 , wherein the inflammation in the lungs is caused by a condition selected from a central nervous system (CNS) injury, a neurodegenerative disease, an autoimmune disease, asthma, chronic obstructive pulmonary disease, cystic fibrosis, interstitial lung disease and acute respiratory distress syndrome. 
     
     
         3 . The method of  claim 2 , wherein the CNS injury is selected from the group consisting of traumatic brain injury (TBI), stroke and spinal cord injury (SCI). 
     
     
         4 . The method of  claim 2 , wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson's disease (PD). 
     
     
         5 . The method of any one of the above claims, wherein the administration of the composition results in inhibition of inflammasome activation in lung cells of the patient. 
     
     
         6 . The method of any one of  claims 1 - 4 , wherein the administration of the composition results in a reduction of caspase-1, nucleotide-binding leucine-rich repeat pyrin domain containing protein 1 (NLRP1), nucleotide-binding leucine-rich repeat pyrin domain containing protein 2 (NLRP2), nucleotide-binding leucine-rich repeat pyrin domain containing protein 3 (NLRP3), NLR family CARD domain-containing protein 4 (NLRC4), caspase-11, X-linked inhibitor of apoptosis protein (XIAP), pannexin-1, Apoptosis-associated Spec-like protein containing a Caspase Activating Recruitment Domain (ASC), interleukin-18 (IL-18), high mobility group box 1 (HMGB1) or absent in melanoma 2 (AIM2) levels in lung cells of the patient as compared to a control, wherein the control is an untreated patient. 
     
     
         7 . The method of  claim 5  or  6 , wherein the lung cells are Type II alveolar cells. 
     
     
         8 . The method of any one of  claims 1 - 5 , wherein the administration of the composition results in a reduction in acute lung injury (ALI) as compared to a control, wherein the control is an untreated patient. 
     
     
         9 . The method of  claim 8 , wherein the reduction in ALI is evidenced by a reduction in neutrophil infiltration into alveolar and/or interstitial space, reduced or absent alveolar septal thickening or a combination thereof. 
     
     
         10 . The method of any one of the above claims, wherein the agent is an extracellular vesicle (EV) uptake inhibitor, an antibody that binds to an inflammasome component or a combination thereof. 
     
     
         11 . The method of  claim 10 , wherein the EV uptake inhibitor is a compound or an antibody, wherein the antibody is selected from Table 1. 
     
     
         12 . The method of any of  claims 10 - 11 , wherein the agent is an EV uptake inhibitor in combination with an antibody that binds to an inflammasome component. 
     
     
         13 . The method of  claim 12 , wherein the EV uptake inhibitor is a heparin. 
     
     
         14 . The method of  claim 13 , wherein the heparin is Enoxaparin. 
     
     
         15 . The method of any of  claims 10 - 14 , wherein the antibody that binds to an inflammasome component is an antibody that specifically binds to a component of a mammalian AIM2, NLRP1, NLRP2, NLRP3 or NLRC4 inflammasome. 
     
     
         16 . The method of  claim 10  or  15 , wherein the inflammasome component is caspase-1, ASC or AIM2. 
     
     
         17 . The method of  claim 16 , wherein the inflammasome component is ASC. 
     
     
         18 . The method of  claim 17 , wherein the antibody binds to an N-terminal PYRIN-PAAD-DAPIN domain (PYD), C-terminal caspase-recruitment domain (CARD) domain or an epitope derived from the PYD or CARD domain of the ASC protein. 
     
     
         19 . The method of  claim 17 , wherein the antibody binds to an amino acid having at least 85% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2. 
     
     
         20 . The method of any of  claims 17 - 19 , wherein the antibody inhibits ASC activity in the lungs of the patient. 
     
     
         21 . The method of any one of the above claims, wherein the composition is formulated with a pharmaceutically acceptable carrier or diluent. 
     
     
         22 . The method of any one of the above claims, wherein the composition is administered intracerebroventricularly, intraperitoneally, intravenously or by inhalation. 
     
     
         23 . A method of treating inflammation in lungs of a patient that has been subjected to a central nervous system (CNS) injury, the method comprising: administering to the patient a composition comprising an agent that inhibits inflammasome signaling, whereby the inflammation in the lungs of the patient is treated. 
     
     
         24 . The method of  claim 23 , wherein the CNS injury is selected from the group consisting of traumatic brain injury (TBI), stroke and spinal cord injury (SCI). 
     
     
         25 . The method of any one of  claims 23 - 24 , wherein the administration of the composition results in inhibition of inflammasome activation in lung cells of the patient. 
     
     
         26 . The method of any one of  claims 23 - 24 , wherein the administration of the composition results in a reduction of caspase-1, NLRP1, NLRP2, NLRP3, NLRC4, caspase-11, XIAP, pannexin-1, Apoptosis-associated Spec-like protein containing a Caspase Activating Recruitment Domain (ASC), interleukin-18 (IL-18), high mobility group box 1 (HMGB1) or absent in melanoma 2 (AIM2) levels in lung cells of the patient as compared to a control, wherein the control is an untreated patient. 
     
     
         27 . The method of  claim 25  or  26 , wherein the lung cells are Type II alveolar cells. 
     
     
         28 . The method of any one of  claims 23 - 27 , wherein the administration of the composition results in a reduction in acute lung injury (ALI) as compared to a control, wherein the control is an untreated patient. 
     
     
         29 . The method of  claim 28 , wherein the reduction in ALI is evidenced by a reduction in neutrophil infiltration into alveolar and/or interstitial space, reduced or absent alveolar septal thickening or a combination thereof. 
     
     
         30 . The method of any one of  claims 23 - 29 , wherein the agent is an extracellular vesicle (EV) uptake inhibitor, an antibody that binds to an inflammasome component or a combination thereof. 
     
     
         31 . The method of  claim 30 , wherein the EV uptake inhibitor is a compound or an antibody, wherein the antibody is selected from Table 1. 
     
     
         32 . The method of any of  claims 30 - 31 , wherein the agent is an EV uptake inhibitor in combination with an antibody that binds to an inflammasome component. 
     
     
         33 . The method of  claim 32 , wherein the EV uptake inhibitor is a heparin. 
     
     
         34 . The method of  claim 33 , wherein the heparin is Enoxaparin. 
     
     
         35 . The method of any of  claims 30 - 34 , wherein the antibody that binds to an inflammasome component is an antibody that specifically binds to a component of a mammalian AIM2, NLRP1, NLRP2, NLRP3 or NLRC4 inflammasome. 
     
     
         36 . The method of  claim 30  or  35 , wherein the inflammasome component is caspase-1, ASC or AIM2. 
     
     
         37 . The method of  claim 36 , wherein the inflammasome component is ASC. 
     
     
         38 . The method of  claim 37 , wherein the antibody binds to the PYD, CARD domain or an epitope derived from the PYD or CARD domain of the ASC protein. 
     
     
         39 . The method of  claim 37 , wherein the antibody binds to an amino acid having at least 85% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2. 
     
     
         40 . The method of any of  claims 37 - 39 , wherein the antibody inhibits ASC activity in the lungs of the patient. 
     
     
         41 . The method of any one of  claims 23 - 40 , wherein the composition is formulated with a pharmaceutically acceptable carrier or diluent. 
     
     
         42 . The method of any one of  claims 23 - 41 , wherein the composition is administered intracerebroventricularly, intraperitoneally, intravenously or by inhalation.